Devices and methods for modulating brain activity

ABSTRACT

Devices and methods for brain modulation are provided herein. A device may comprise a body and components for activating the brain. Such components include ultrasound transducers. The devices are used to provide ultrasound waves to brain structures in a subject wearing a device for methods to treat traumatic brain injury, affect postural control, affect wakefulness, attention, and alertness, to provide memory control, to alter cerebrovascular hemodynamics, to minimize stress, and to reinforce behavioral actions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/211,143, filed Dec. 5, 2018, now U.S. Patent Application PublicationNo. 2019/0105517, which is a continuation of U.S. patent applicationSer. No. 15/014,805, filed Feb. 3, 2016, now U.S. Patent ApplicationPublication No. 2016/0220850, which is a continuation application ofU.S. patent application Ser. No. 13/453,179, filed Apr. 23, 2012, nowU.S. Patent Application Publication No. 2012/0289869, which is acontinuation of PCT/US2010/055527, filed Nov. 4, 2010, which claims thebenefit of U.S. Provisional Patent Application No. 61/257,915, filedNov. 4, 2009, the contents of which are incorporated herein in theirentirety.

FIELD

The present invention is directed to devices and methods for modulatingbrain activity using ultrasound, particularly devices and methods thatprovide ultrasound wavelengths to neural tissues.

BACKGROUND

Ultrasound (US) has been used for many medical applications, and isgenerally known as cyclic sound pressure with a frequency greater thanthe upper limit of human hearing. The production of ultrasound is usedin many different fields, typically to penetrate a medium and measurethe reflection signature or to supply focused energy. For example, thereflection signature can reveal details about the inner structure of themedium. A well known application of this technique is its use insonography to produce a picture of a fetus in a womb. There are otherapplications which may provide therapeutic effects, such as lithotripsyfor ablation of kidney stones or high-intensity focused ultrasound forthermal ablation of brain tumors.

A benefit of ultrasound therapy is its non-invasive nature.Neuromodulation techniques such as deep brain stimulation (DBS) andrepetitive transcranial magnetic stimulation have gained attention dueto their therapeutic utility in the management of numerousneurological/psychiatric diseases. These methods for stimulatingneuronal circuits have been demonstrated to hold promise for thetreatment of such diseases and disorders as Parkinson's, Alzheimer's,coma, epilepsy, stroke, depression, schizophrenia, addiction, neurogenicpain, cognitive/memory dysfunction, and others.

What is needed are devices that can provide effective ultrasound therapyto neural tissue, such as the brain, for continuous or short-termapplications. Devices that could provide treatments shortly after injuryto neural tissue would also be desirable.

SUMMARY OF THE DISCLOSURE

The present invention comprises methods and devices for modulating theactivity or activities of the brain in humans and other organisms.Methods of the present invention comprise application of ultrasound (US)to the brain to affect the brain and modulate the brain's activities.Devices of the present invention comprise an ultrasound device operablyattached to or associated with a head containing a brain, the ultrasounddevice may comprise one or more components for generating ultrasoundwaves, such as ultrasonic emitters, transducers, piezoelectrictransducers, piezopolymer transducers, composite transducers, gas matrixpiezoelectric transducers, CMUTs (capacitive micromachined ultrasoundtransducers), and may be provided as single or multiple transducers orin array configurations. Ultrasound transducer elements may alsocomprise focusing lenses such as acoustic hyperlenses or metamaterialswhen providing ultrasound waves to affect brain regions. The lenses ormetamaterials are useful for brain regions with a size below wavelengthdiffraction limits of some ultrasound used to treat the brain targets.Optionally, the ultrasound device may comprise power sources, componentsfor transmitting or receiving data, components for remote activation ofthe ultrasound transducers or other components, global positioningcomponents or other location or tracking components. The ultrasoundwaves provided may be of any shape, and may be focused or unfocused,depending on the application desired. The ultrasound may be at anintensity in a range of about 0.0001 mW/cm² to about 100 W/cm² and anultrasound frequency in a range of about 0.02 to about 10.0 MHz at thesite of the tissue to be modulated.

Methods of the present invention comprise modulating brain activity byproviding ultrasound waves to the brain, or particular brain regions, orbrain efferents or brain afferents of one or more regions, orcombinations thereof, at an effective intensity and for an effectivetime range so that the brain activity is altered. It is contemplatedthat an ultrasound device that is operably attached to the subject, suchas an ultrasound device comprising a helmet comprising at leastultrasound generating components, is used to provide the ultrasoundtreatments described herein. Such ultrasound methods and treatmentsdescribed herein may also be provided to a subject using ultrasoundcomponents that are not incorporated into a wearable device, but areattached directly to the subject or are at some physical distance fromthe subject.

Methods comprise modulating brain activity in a subject by providing aneffective amount of at least ultrasound waves to one or more brainstructures, for example, by using an ultrasound device, a BRI (BrainRegulation Interface), disclosed herein. A method comprises treating orameliorating the effects of trauma to the brain by providing aneffective amount of ultrasound to a brain region that has receivedtrauma or to a surrounding or remote brain area that may be affected bythe trauma. Such a method can reduce the secondary effects of traumaticbrain injury. A method comprises impeding or inhibiting memory formationin a subject. A method comprises facilitating the formation of memories.A method of the present invention comprises altering a stress responsein a subject. A method comprises activating arousal brain areas toincrease alertness, awareness, attention or long-term wakefulness in asubject. A method comprises activation of reward pathways in a subject.Methods of the present invention comprise activation of reward pathways,activating sensory or motor brain regions, and methods for treatinghumans and animals. Methods of the present invention may comprisecombinations of the methods taught herein, and wherein ultrasound isprovided by an ultrasound device disclosed herein. Methods disclosedherein may be accomplished by ultrasound devices known to those skilledin the art.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments and togetherwith the description illustrate the disclosed compositions and methods.

FIG. 1A-E are diagrams that illustrate exemplary systems and devices formodulating brain activity. 1A shows device comprising ultrasoundtransducers, 1B shows a cross-section of the body portion and thetransducers of 1A. FIG. 1C shows a chassis-type body for attachment oftransducers, FIG. 1D shows the chassis attached within a helmet, andFIG. 1E shows the chassis positioned on a subject.

FIG. 2 shows an exemplary embodiment of an ultrasound device of thepresent invention comprising components that provide both ultrasound andelectromagnetic energy to the brain.

FIG. 3 illustrates an exemplary embodiment of a pulsing strategy used togenerate ultrasound stimulus waveforms that provide ultrasound energy tothe brain or neural tissue for modulation of activity.

FIG. 4 is a flow chart showing a brain regulation interface (BRI) deviceof the present invention and exemplary components that the device maycomprise.

FIG. 5 illustrates an exemplary ultrasound device comprising a pluralityof components for modulation of brain activity, for monitoring brainactivity and for transmitting and receiving information about thesubject's physical location and/or vital statistics such as bloodpressure, heart rate, respiration rate, and/or blood oxygenation levels.The illustration also illustrates components that may be used with abrain regulation interface (BRI) device including ultrasoundtransducers, magnetic transducers, light emitting devices, andcommunication devices.

FIG. 6 illustrates an exemplary ultrasound device (BRI) comprisinglocational or global positioning components.

FIG. 7 illustrates an exemplary ultrasound device having movable orrotatable components, such as a movable or rotatable ultrasoundtransducer.

FIG. 8A-F illustrates exemplary arrangements of phased arraytransducers.

FIG. 9A-B are graphs showing the energy produced in the conversion ofmechanical energy to electrical energy using piezopolymers.

FIG. 10A-B illustrate exemplary examples of an acoustic hyperlens (A)and such an acoustic hyperlens or metamaterials attached to ultrasoundtransducers and an ultrasound device (B) for achieving subdiffractionspatial resolutions in treating very small brain regions withultrasound.

FIG. 11A-C shows ultrasound stimulus waveforms for the transcranialstimulation of intact brain circuits (A) Illustration of the method usedto construct and transmit pulsed US waveforms into the intact mousebrain. Two function generators were connected in series and used toconstruct stimulus waveforms. An RF amplifier was then used to providefinal voltages to US transducers. (B) An example low-intensity USstimulus waveform is illustrated to highlight the parameters used intheir construction. The acoustic intensities generated by theillustrated stimulus waveform are shown in the yellow box. (C) Projectedfrom a transducer surface to the face of a calibrated hydrophone, theacoustic pressure generated by a 100 cycle pulse of 0.5 MHz ultrasoundis shown (left). The pressure generated by the same US pulse whentransmitted from the face of the transducer through a fresh ex vivomouse head to regions corresponding to motor cortex (0.8 mm deep) isshown (right).

FIG. 12A-D shows low-intensity pulsed US stimulates neuronal activity inthe intact mouse motor cortex (A) The coronal brain section shows anelectrolytic lesion illustrating a recording site from which US-evokedneuronal activity was acquired in M1. (B) (Top) Raw (black) and average(gray; 25 trials) US-evoked MUA recorded from M1 cortex in response tothe delivery of pulsed US waveforms. (Middle) Addition of TTX to thecortex reduced synaptic noise and attenuated US-evoked MUA. (Bottom) Rawcontrol (black), average control (green), and average TTX (red) LFPrecorded from M1 cortex in response to 25 US stimulus waveformsdelivered every 10 s. (C) The spike raster plot illustrates the increaseof cortical spiking as a function of time in response to 25 consecutiveUS stimulation trials. (D) A poststimulus time histogram illustrates theaverage MUA spike count recorded 500 ms prior to and 500 ms followingthe delivery of US stimulus waveforms to motor cortex. Data shown aremean±SEM.

FIG. 13A-E shows transcranial stimulation of motor cortex with pulsed USfunctionally activates descending corticospinal motor circuits in intactmice. (A) Raw (left) and full-wave rectified (FWR; right) EMG tracesobtained for a spontaneous muscle twitch (top) and average (ten trials)increase in muscle activity produced by transcranial US stimulation ofmotor cortex (bottom).The duration of the US stimulus wave-form (black),average US-evoked EMG trace (gray), and EMG integral (gray dashed line)are shown superimposed at lower right. (B) EMG response latencies (top)and amplitudes (bottom) recorded from the left triceps brachii inresponse to right motor cortex stimulation are plotted as a function oftrial number repeated at 0.1 Hz. Individual US-evoked raw EMG traces areshown for different trials (right). (C) EMG failure probabilityhistograms are shown for four progressively increasing stimulusrepetition frequencies (left;). Raw US-evoked EMG traces are shown fortwo different stimulus repetition frequencies (right). Data shown aremean±SEM. (D) Raw EMG traces illustrating application of TTX to themotor cortex blocks US-evoked descending corticospinal circuit activity.(E) Raw (black) and averaged (gray; ten trials) temperature recordingsobtained from motor cortex in response to transmission of US waveformswith short pulse durations (PD) used in stimulus waveforms (top).Similarly, temperature recordings of cortex in response to waveformshaving a PD ˜100 times longer than those used in stimulus waveforms(middle and bottom).

FIG. 14A-C shows interactions of the acoustic frequency and acousticintensity of stimulus waveforms on descending corticospinal circuitactivation. (A) Maximum-peak normalized (Norm) US-evoked EMG amplitudehistograms are plotted for the four US frequencies used in theconstruction of stimulus waveforms. Data shown are mean±SEM.(B) Meanmaximum-peak normalized US-evoked EMG amplitudes are plotted as afunction of US intensities (/_(SPTA)) produced by 20 distinct stimuluswave-forms (see Table S1).(C) The interaction between US intensity(/_(SPTA)) and US frequency is plotted as a function of maximum-peaknormalized EMG amplitudes (pseudocolor LUT).

FIG. 15A-E shows spatial distribution of neuronal activation triggeredby transcranial pulsed US. (A) Diagrams showing the anatomical locationswhere transcranial pulsed US was delivered through an acousticcollimator (green; d=2 mm) and the brain volume subsequentlyreconstructed (blue) to develop functional activity maps usingantibodies against c-fos. (B) Light micrographs showing c-fos activityin a coronal brain section at different locations inside (i) and outside(ii and iii) the US transmission path. (C) A psuedocolored map of c-fos+cell densities in 250×250 μm regions is shown for a reconstructedcoronal section obtained from within the stimulus zone. Small regionsinside (i) and outside (ii and iii) the US brain transmission path arehighlighted and contain c-fos density data obtained from thecorresponding images shown in (B). (D) Similar psuedocolored c-fosactivity maps are shown for coronal brain sections rostral (left) andcaudal (right) to the stimulated brain regions. (E) The line plotsillustrate the mean c-fos+ cell densities observed along therostral-caudal axis of reconstructed brain volumes for stimulated(black) and contralateral control hemispheres (gray). Regions of cortexwithin the stimulation zone are indicated in red. Data shown aremean±SEM.

FIG. 16A-D shows FIG. 7. transcranial stimulation of the intact mousehippocampus with pulsed ultrasound (A) Shown is an illustration of thegeometrical configuration used for targeting the dorsolateralhippocampus with transcranial pulsed US while recording evokedelectro-physiological responses in the dorsal hippocampus (left). Alesion illustrates the site of an electrophysiological recordinglocation in the hippocampal CA1 s.p. region (right). (B) Raw (black) andaverage (cyan) hippocampal CA1 LFP recorded in response to 50consecutive US stimulation trials (left). A pseudocolored spike-densityplot illustrates the increase in CA1 s.p. spiking as a function of timein response to 50 consecutive pulsed US stimuli delivered at 0.1 Hz(right). (C) An individual recording trace of CA1 s.p. extracellularactivity in response to a pulsed US waveform is shown in its wideband(top), gamma (middle), and SWP (bottom) frequency bands. An expanded 250ms region of the SWP trace (red) illustrates SWP “ripples”. (D) Confocalimages illustrating BDNF (green) expression in the CA1 s.p. (top) andCA3 s.p. (bottom) regions of hippocampus from contralateral control(left) and stimulated hemispheres (right). Histograms (far right)illustrate the significant increase in the density of BDNF+ punctatriggered by transcranial US stimulation for the CA1 s.p. (top) and CA3s.p. (bottom) regions of hippocampus. Data shown are mean±SEM.

FIG. 17A-B shows the results of using ultrasound to modify cognitiveperformance. (A) Shows the stimulus strategy used stimulating thehippocampi of mice with transcranial pulsed ultrasound prior to theirtraining (four trials per day for three consecutive days) on a spatiallearning task the Morris Water Maze. (B) Task learning acquisitioncurves show a decreasing mean platform escape latency across days forboth the sham treated and US stimulated mice (left). As can be seen bythe line plot (left), mice stimulated with US (red) just prior totraining learned the task slower compared to sham treated controls(black) as indicated by their slower acquisition rates or slowerdecreasing escape latency times. The data showing mean escape latenciesfor the treatment groups (US stimulated and sham control) are shown forthe four individual trials across the three training days. The line plot(middle) shows an increase in the escape latency observed from trial 4on day 1 to trial 1 on day 2 for US stimulated mice (red) compared tosham controls (black). These data illustrate that mice stimulated withUS have more pronounced “forgetting” or disrupted memory consolidationprocesses compared to sham treated controls, which retain escapelatencies across the ˜22 hour delay between the end of trial 4 on day 1and the beginning of trial 1 on day 2. On the day following three daysof Morris Water Maze training, mice underwent a test in which the escapeplatform was removed from the maze. The time spent searching in thewater maze quadrant where the escape platform had been located ontraining days was quantified and is shown in the histogram (right). Theshorter times spent in the correct quadrant for US stimulated micecompared to sham controls indicates that US stimulation occurring attimes near the acquisition of information (learning; prior to MorrisWater Maze training in this case) can disrupt the memory orconsolidation of that information.

FIG. 18A-18B shows the results of using ultrasound to enhance cognitiveprocesses. (A) A strategy is illustrated by which naive mice had theirhippocampi stimulated with transcranial pulsed US for 5 minutes per dayfor 7 consecutive days prior to beginning training on a spatialcognition task the Morris Water Maze. As illustrated, mice were thentrained on a Morris Water Maze task without receiving further USstimulation before being tested on the Morris Water Maze task. (B) Theline plot (left) shows that chronic brain stimulation (7 days in thiscase) with transcranial pulsed US can enhance learning as indicated bythe faster task acquisition rates or faster decreasing escape latencytimes on the Morris Water Maze for US stimulated mice (red) compared tosham treated controls (black). On the day following three days of MorrisWater Maze training, mice underwent a test in which the escape platformwas removed from the maze. The time spent searching in the water mazequadrant where the escape platform had been located on training days wasquantified and is shown in the histogram (right). The longer times spentin the correct quadrant for US stimulated mice compared to sham controlsindicates that chronic US stimulation not occurring at times near theacquisition of information (learning; prior to Morris Water Mazetraining in this case) can enhance the memory or consolidation of thatinformation. Thus, depending on the stimulation paradigm transcranialpulsed ultrasound delivered through brain regulation devices can be usedto either enhance or impair cognitive processes such as learning andmemory.

FIG. 19A-C illustrates that transcranial pulsed ultrasound can be usedto modulate brain activity to study and or treat neurological diseases.(A) Shows EMG recordings in response to transcranial ultrasound stimulidelivered to the brain of normal mice in a continuous wave mode for 5seconds. The brain activity pattern stimulated by continuous wavetranscranial ultrasound is indicative of that observed during epilepticseizure activity. Such seizure activity patterns are known to occur forten seconds or longer following the onset of a brain stimulus as shownby the EMG traces in response to transcranial stimulation of braintissues with continuous wave ultrasound. Evoking such seizure activitypatterns can be helpful in studying epilepsy by mapping diseased orprone circuits, as well as by using US to modulate brain activitypatterns to screen for pharmacological compounds or genes useful fortreating abnormal brain activity. When compared to the activity patternsillustrated in FIGS. 12-16 produced with pulsed ultrasound, the data inpanel (A) triggered with continuous wave ultrasound show thattranscranial ultrasound can influence brain activity in radicallydifferent manners depending on the ultrasound stimulus waveform used anddepending on the desired outcome. (B) A mouse is shown at leftimmediately after being injected with kainic acid to produce a standardmodel of epilepsy. EMG activity before (top right) and after (bottomright) the onset of epileptic seizure activity is illustrated. The EMGtraces on the bottom right show the presence of seizure activity asindicated by the increased persistent EMG activity compared to thepre-seizure trace on the top right. (C) EMG traces showing that brainstimulation achieved with transcranial ultrasound can be used toterminate seizure activity in a mouse model of epilepsy. Four differentexamples illustrate the delivery of transcranial ultrasound is capableof quickly attenuating pronounced seizure activity as indicated by thedecreasing EMG amplitude soon after the delivery of a transcranialultrasound stimulus waveform. Such an effect of ultrasound on diseasedbrain activity can be administered manually in response to seizuresdetected visually or by way of EEG or EMG activity. In anotherembodiment of the present invention, the delivery of ultrasound to thebrain can be controlled automatically in response to seizure activitydetected by EEG, EMG, MEG, MRI, or other readout of brain activity.

FIG. 20A-B show A-an exemplary embodiment for treating peripheralnerves. The dark circles represent ultrasound transducers forstimulating peripheral nerve structures to evoke mechanical, thermal, orpainful sensations, which are processed by the brain and result in achange in brain activity to process the stimulus. B-Different skinreceptors making up the nervous system are shown. These nerve structurereceptors can be differentially modulated by ultrasound to evokedifferent types of somatosensory feedback cues, which are interpreted bythe brain. Such sensations can be pain, heat, cold, light touch, deeppressure, or other mechanical sensation.

DETAILED DESCRIPTION

The present invention comprises methods and devices for modulating theactivity of the brain of humans or animals. The methods and devicescomprise use of ultrasound waves directed to the brain in livingsubjects. Methods of the present invention comprise providing aneffective amount of ultrasound waves, such as low intensity, lowfrequency ultrasound, low intensity ultrasound, or other intensity orfrequency ultrasound to the brain to affect the brain and modulate thebrain's activities, and to alter or control physiological or behavioralresponses by the body of the subject.

Devices of the present invention comprise a device operably connected tothe subject comprising one or more components for generating ultrasoundwaves, herein referred to as transducers, and including but not limitedto, ultrasonic emitters, transducers or piezoelectric transducers,piezocomposite transducers, piezopolymers, CMUTs (capacitivemicromachined ultrasound transducers), and which may be provided assingle or multiple transducers or in array configurations. Theultrasound waves provided may be of any shape or amplitude, and may befocused or unfocused, depending on the application desired. Theultrasound may be at an intensity in a range of about 0.0001 mW/cm² toabout 100 W/cm² and an ultrasound frequency in a range of about 0.02 MHzto about 10.0 MHz at the site of the cells or tissue to be modulated.

One or more cooling components may be incorporated into the body of thedevice, or may be placed on the scalp before, during or after providingultrasound waves to the head. A cooling component may be ultrasoundtransparent, so that the waveforms, intensity and/or frequency are notaltered by the cooling component. A cooling component may be an ice bag;a freezable container that is chilled by placing in a cold location,such as a freezer; a container of chemicals such that a chemicalreaction can be initiated that is endothermic and cools the container; amechanically chilled material or container which is cooled by mechanicalmeans; or any other material or container known in the art that mayprovide a cool or cold surface that may be applied to the head of asubject.

As disclosed herein, aspects of the invention are described in thecontext of providing ultrasound to mammalian brain tissue, whichincludes specific regions of the brain, or brain afferents or brainefferents, or providing ultrasound to one or more brain regions,combinations of these, or to cause alterations in synthesis, release oruptake of neurotransmitters. For example, the brain may comprise tissuewith neurons within it located in the head region, neural precursorcells, such as neural stem cells, neurons, axons, neural cell bodies,ganglia, dendrites, synaptic regions, neuronal tissue, or other cellspositioned in the brain of a living organism among neurons, such asglial cells, oligodendrites, or astrocytes. Treatments of neural cellsis disclosed in PCT/US2009/050560, which is incorporated herein in itsentirety.

Ultrasound has been shown to influence neuronal activity by suppressingthe amplitudes and/or conduction velocity of evoked action potentials.The use of moderate and high intensity, high-frequency ultrasound andlong exposure times to control neuronal activity minimizes ultrasound'spracticality for modulating neuronal activity in living organisms. Thepresent invention comprises methods for low-intensity (<500 mW/cm²),low-frequency ultrasound (<0.9 MHz) and effects on cellular modulation,such as methods for influencing neuronal activity. For example, lowintensity may comprise about 450 mW/cm², 400 mW/cm², 350 mW/cm², 300mW/cm², 250 mW/cm², 200 mW/cm², 150 mW/cm², 100mW/cm², 50 mW/cm², 25mW/cm², 10 mW/cm², and levels of ultrasound intensity within thesestated amounts, including from about 450 m W/cm² to about 1 mW/cm².Other intensities that are contemplated by the present inventioncomprise from about 1 W/cm2 to about 100 W/cm². For example, an acousticintensity of the present invention may comprise about 1 W/cm², about 2W/cm², about 3 W/cm², about 4 W/cm², about 5 W/cm², about 10 W/cm²,about 15 W/cm², about 20 W/cm², about 25 W/cm², about 30 W/cm², about 40W/cm², about 50 W/cm², about 60 W/cm², about 70 W/cm², about 75 W/cm²,about 80 W/cm², about 90 W/cm², about 100 W/cm², or in a range of about10 mW/cm² to about 500 mW/cm². Low frequency ultrasound may compriseranges from about 0.88 MHz to about 0.01 MHz, from about 0.80 MHz toabout 0.01 MHz, 0.80 MHz to about 0.1 MHz, from about 0.70 MHz to about0.1 MHz, from about 0.60 MHz to about 0.1 MHz, from about 0.50 MHz toabout 0.1 MHz, from about 0.40 MHz to about 0.1 MHz, from about 0.30 MHzto about 0.1 MHz, from about 0.20 MHz to about 0.1 MHz, from about 0.10MHz to about 1.0 MHz, and ultrasound frequencies within these ranges.Other frequencies contemplated by the present invention comprise rangesfrom about 0.1 MHz to about 1.5 MHz, from about 0.1 to about 1.3 MHz,from about 0.1 to about 1.0 MHz, from about 0.1 to about 0.9 MHz, fromabout 0.1 to about 0.8 MHz, from about 0.1 to about 0.5 MHz, from about0.1 to about 0.4 MHz, from about 0.5 to about 1.5 MHz, from about 0.7 toabout 1.5 MHz, from about 1.0 to about 1.5 MHz, from about 0.02 MHz toabout 10 MHz, and ultrasound frequencies within these ranges.

As used herein, the cited intensities and frequencies are the intensityand frequency levels at the target tissue site, not the actual outputnumber of the transducer. For example, the pressure waveform experiencedat the site of the target tissue would have a frequency below about0.9MHz and an intensity below about 900 mW/cm². The output of atransducer may have to be much larger than the resulting effectiveamount at the target tissue site. For example, a transducer may output0.9 MHz ultrasound at about 90 W for transmission through an intactscalp and skull for the effective amount at the brain tissues beingtreated to be about 0.9 MHz and below about 900 mW/cm², as the skullabsorbs a significant portion of ultrasound waves. Thus, the frequenciesand intensities stated and claimed herein are the frequencies andintensities experienced at the target tissue site, not the output of theultrasound transducers.

As used herein, providing ultrasound waves to a target site to modulatebrain activity comprises providing an ultrasound stimulus waveform to asubject. The ultrasound stimulus waveform may also alternatively bereferred to herein as a waveform, and the two terms are usedinterchangeably as can be understood by those skilled in the art. Asused herein, modulating brain activity means altering the brain activityin one or more sites of the brain. The brain activity may be increasedor decreased by the action of at least the ultrasound waves, which mayinclude increasing or decreasing neuron firing, receptivity, release oruptake of neurohormones, neurotransmitters or neuromodulators, increaseor decrease gene transcription, protein translation or proteinphosphorylation or cell trafficking of proteins or mRNA, or affect theactivity of other brain cell or structure activity.

A stimulus waveform may be provided to a subject, human, animal or othersubjects, once or multiple times in a single treatment, or in acontinuous treatment regimen that continues for a day, days, weeks,months, years, or for the life of the subject. Determining the length oftreatment needed is within the skills of medical and/or researchprofessionals. It is contemplated by the present invention that astimulus waveform may be pulsed or continuous, have one or multiplefrequencies, and other characteristics as described herein. For example,in particular methods, a pulsed ultrasound stimulus waveform may betransmitted for about 10 microseconds, for about 25 microseconds, forabout 50 microseconds, for about 100 microseconds, for about 250microseconds, for about 500 microseconds, for about 1000 microseconds,for about 2000 microseconds, for about 3000 microseconds, for about 4000microseconds, for about 5000 microseconds, for about 1 second, for about2 seconds, for about 3 seconds, for about 4 seconds, for about 5seconds, for about 6 seconds, for about 7 seconds, for about 8 seconds,for about 9 seconds, for about 10 seconds, and then this treatment maybe repeated for the same or a different length of time, one or moretimes. For example, a stimulus waveform may be provided every 11 secondsfor a duration of about 250 microseconds for years, or for the life ofthe subject.

FIG. 3 illustrates ultrasound waves in a graph that illustrates anexample ultrasound waveform 200 for modulating neural activity,according to an embodiment. The horizontal axis 202 indicates time, andthe vertical axis 204 indicates pressure, both in arbitrary units. Themodulating waveform 200 contains one or more pulses, such as pulse 220 aand pulse 220 b and pulse 220 c. Each pulse includes one or more cyclesat an ultrasound frequency. For example, pulse 220 a includes fivecycles of an ultrasound frequency with a period (τ) 210 in seconds equalto the reciprocal of the frequency (f) in Hertz (i.e., τ=1/j). Thenumber of cycles in a pulse is designated cycles per pulse (c/p). Thepulse length 222 is designated PL and is given in seconds by the productof the period t and number of cycles per pulse c/p, i.e., PL=τ* c/p.

Pulses are separated by quiescent periods that are related to the timebetween pulse starts, shown in FIG. 3 as pulse repeat time 230. Thereciprocal of the pulse repeat time 230 in seconds is the pulse repeatrate in Hertz, designated herein the pulse repeat frequency PRF, todistinguish it from the ultrasound frequency f. In some embodiments, thepulse repeat frequency PRF is a constant for a waveform 200. In someembodiments, the pulse repeat frequency PRF increases from a minimum(PRFmin) to a maximum (PRFmax) over a time interval called a ramp time.For example, in some embodiments, PRF increases from PRFmin=0 toPRFmax=3000 Hz over ramp time=5 seconds. In other embodiments the PRF isnot swept and may range from 0.001 kHz to 900 KHz. The waveformcontinues for a waveform duration 234 that ends with the last pulse inthe waveform. The number of pulses in the waveform is designated Np.

The pressure amplitude of the ultrasound wave is proportional to avoltage range used to drive a piezoelectric transducer(s), for example alead zirconate titanate (PZT) transducer or other piezoelectric element.For example, a voltage range may be selected between 100 milliVolts (mV,1 mV=10⁻³ Volts) and 50 V, which correspond to intensity levels lessthan 500 mW/cm² depending on the sensitivity and output characteristicsof the transducer(s) used Although pulses may be sine waves having asingle ultrasound frequency herein, other oscillating shapes may beused, such as square waves, or spikes, or ramps, or a pulse includesmultiple ultrasound frequencies composed of beat frequencies, harmonics,or a combination of frequencies generated by constructive ordeconstructive interference techniques, or some or all of theaforementioned.

The present invention comprises devices, methods using such devices, andsystems for modulation of brain structures, which results in modulationof the activities of such structures. Such devices, systems and methodscomprise providing ultrasound waves to brain structures, cells or othertissues. Exemplary embodiments of devices and methods of the presentinvention are provided herein. Methods comprise providing ultrasound toa subject, for example, by the use of one or more low intensity, lowfrequency ultrasound and/or low intensity ultrasound, or one or moreother ultrasound intensity or frequency transducers. For example, anultrasound (US) transducer can be acoustically coupled to an externalsurface of a subject, or alternatively, the US transducer can be in anacoustically effective range of the target tissue. The ultrasoundtransducer is then be driven to form stimulus waveforms in the tissue,cell, or organ, for example with an intensity below about 100 Watts persquare centimeter (mW/cm²), below about 1 W/cm², or below about 500mW/cm². The ultrasound waveforms may comprise one or multiplefrequencies.

In an embodiment, driving the ultrasound transducer comprises drivingthe ultrasound transducer to form a pressure fluctuation waveform or astimulus waveform including a plurality of pulses, each pulse ofduration less than about 10000 microseconds (p). Pulse duration may bevariable depending on a particular method or device, and may have aduration of about 10 seconds or less, such as about 100 to 10000microseconds. Driving the ultrasound transducer may comprise driving theultrasound transducers to form a pressure fluctuation waveform or astimulus waveform with a plurality of pulses within a waveform durationthat is less than about ten second (s). This comprises only one stimuluswaveform and this waveform may be repeated a nearly infinite number oftimes. As used herein, pressure fluctuation waveform and stimuluswaveform are used interchangeably.

Driving the ultrasound transducer may comprise driving the ultrasoundtransducers to form a stimulus waveform at a frequency above about 0.20MHz. The waveform may be one or more of known waveforms arbitrary ornot, including but not limited to, sine, square, sawtooth, triangle,ramps and spikes. The ultrasound waves may be focused to provide actionat a particular site in or on the subject, or focused at more than onesite, or the waves may be unfocused and provide action at multiplesites. The waves may be continuous or pulsed, depending on the desiredapplication. The frequency or intensity may be uniform throughout atreatment period, or may alternate or sweep from one number to another,and back to the original number. Those skilled in the art are able todetermine such parameters for the desired application. Examples aredisclosed herein.

The acoustic frequency and intensity characteristics of an UNMODstimulus underlie its core effect on brain activity. A broad range ofacoustic frequencies, intensities, and transmission modes have been usedto produce variable excitation and inhibition of neuronal activity. Theacoustic frequencies used to manipulate neuronal activity range from0.25 MHz (Tufail et al., 2010) to 7.0 MHz (Mihran et al., 1990b). Whilelower frequencies of US have longer wavelengths and lower spatialresolutions than higher frequencies, acoustic frequencies <1 MHz forstimulating intact brain circuits using US are a useful range. US <0.7MHz represents the frequency range where optimal gains betweentranscranial transmission and brain absorption of US have been observed(Hayner and Hynynen, 2001; White et al., 2006a, b). In mice, optimalwaveforms for evoking intact brain circuit activity are composed ofacoustic frequencies ranging between 0.25 and 0.50 MHz (Tufail et al.,2010). For these ranges, implementing broadband transducers, which havea center frequency between 0.2 and 0.7 MHz for UNMOD is useful. Use ofimmersion-type (water-matched) transducers coupled to the skin with USgel to minimize acoustic impedance mismatches when transmitting acousticenergy from a transducer into the brain is also contemplated by thepresent invention.

Other waveform variables, in addition to acoustic frequency andtransducer characteristics, such as mode of transmission (continuouswave versus pulsed wave) and pulse profile (cycles per pulse, cp; pulserepetition frequency, PRF; and number of pulses, np) may affect theintensity characteristics of any given US stimulus waveform. Thoseskilled in the art can determine an intensity profile for a stimuluswaveform. In in vitro studies (Tyler et al., 2008), stimulus waveformscomposed of US pulses having a high pulse intensity integral (P//;≈4.0J/cm²) were used, which were repeated at slow PRFs (≈, 50 Hz) for longdurations (≈, 5 sec). Stimulation of brain activity in vivo may useother US waveforms. For example, stimulus waveforms constructed of USpulses having a low P//(<0.1 mJ/cm²), which were repeated at high PRFs(1.0-3.0 kHz) for short durations (<0.4 sec) were effective forstimulating normal brain circuit activity in vivo (Tufail et al., 2010).These two different US pulsing strategies (high P//with a low PRF for invitro stimulation versus a low P/with a high PRF for in vivo), indicatedoptimal US waveforms for triggering brain activity and have low temporalaverage intensity values in a range between 30 and 300 mW/cm².

In addition to the general pulsing strategies described herein, UStransmitted in a continuous wave (CW) mode is capable of influencingbrain activity, and may show different effects and time courses comparedto pulsed US. Short bursts of pulsed US can stimulate brief (tens ofmilliseconds) periods of neuronal activity and US stimuli delivered inCW-mode for 5 seconds can induce seizure activity lasting >20 seconds innormal mice, and can disrupt kainic acid-induced electrographic seizureactivity in epileptic mice. Repeated short bursts of pulsed US canattenuate seizure activity in epileptic mice indicating UNMOD may be ageneral interference source for disrupting aberrant activity. Theinfluence of US stimuli on brain activity patterns may depend onstimulus amplitude, duration, and temporal frequency, as well as theinitial state of the brain when stimulation ensues. The implementationof any particular UNMOD stimulus waveform or transmission approach maydepend on the outcome sought.

Disclosed herein are several methods for delivering US across the skinand skull in order to achieve brain stimulation. For example, an aspectof the present invention comprises use of unfocused US for stimulatingbroad, nonspecific brain regions. A nonspecific brain stimulation methodwith single element planar US transducers can be useful depending on thedesired outcome. For example, unfocused US transmitted from planartransducers may rapidly terminate seizure activity in mice sufferingfrom epilepsy or for treating a variety of other brain diseasesincluding severe or mild traumatic brain injuries.

Transmission of US from the transducer into the brain may occur atpoints where acoustic gel is coupling the transducer to the head. Onemay cover the entire face of the transducer with acoustic gel to preventtransducer face heating and damage. Alternatively, coupling thetransducer to the head through small gel contact points may be aphysical method for transmitting US into restricted brain regions. Thespatial envelope of US transmitted into the brain may be laterallyrestricted by using acoustic collimators. The use of acousticcollimators allows one to stimulate restricted brain regions in atargeted manner. Single element focused transducers may be used fordelivering spatially restricted acoustic pressure fields to brains. Suchsingle element focused transducers can be manufactured having variousfocal lengths depending on the size and center frequency of thetransducer. An aspect of the invention comprises using air-coupledtransducers to deliver transcranial pulsed ultrasound into the brainfrom single-element transducers or from phased arrays as describedbelow. In aspects, gel-filled pads or other fluid filled bladders may beused for acoustically coupling transducers to the skin and or the skullin brain regulation interface designs.

A focusing method may involve the use of multiple transducers operatingin phased arrays to focus US through the skull to specific brainregions. US can be focused through human skulls using phased transducerarrays. Although the spatial resolution for focusing US is currentlylimited by the acoustics or wavelength employed, recent advances infocusing US with adaptive optics (Zhang et al., 2009) allows US to gainspatial resolutions below the diffraction limits, similar to thatrecently achieved in optical microscopy (Abbott, 2009). US may conferspatial resolutions similar those achieved by DBS electrodes. Aspects ofmethods described herein contemplate use of subdiffraction methods usinghyperlenses, metamaterials, and acoustic bullets with nonlinear lenses.

One or more US transducer may function individually or in multiples,such as in one or more arrays. FIG. 8A-F illustrate exemplaryarrangements of phased array transducers. FIG. 8A, shows a specificarrangement of a phased array transducer, for example, made from apiezoelectric material such as polyvinylidene fluoride (PVDF). Thedarker areas represent the active region of the phased array. FIG. 8Bshows a different phased array arrangement containing 24 elements.Different phased array arrangements may contain differing numbers ofelements, any of which can be used in an ultrasound device of thepresent invention. For example, depending on the intended use and theintended brain structure to be targeted, an ultrasound device of thepresent invention may have circular arrays like those of 8 A or B, ormay have arrays arranged in rectangular patterns like those of 8 C or E,or both, as in 8D. Piezoelectric materials can be flat or curved inconvex or concave orientations.

An ultrasound device of the present invention may use any combination ofcurved, concave, convex, or flat phased arrays in any desiredgeometrical shape or arrangement necessary to produce a focused orunfocused ultrasound field in one or more brain regions or structures.Phased arrays may be mounted statically on or in the body of anultrasound device of the present invention, or may have piezoactuatorsor other motion control devices to change the shape and/or position ofone or more transducers or one or more arrays. Such movement controlallows for adjustments or changes to focus the ultrasound fields. Suchadjustments or changes may be made in response to feedback informationreceived from the subject wearer or made by other controllers, such as aremote control site. FIG. 8F illustrates an ultrasound device of thepresent invention comprising multiple phased arrays, wherein two arraysare in a circular arrangement and two arrays are in a rectangulararrangement.

In other aspects of the device or methods, acoustic hyperlenses ormetamaterials may be used to achieve focusing and spatial resolutions ofthe ultrasound waves below the diffraction limits. See FIG. 10 whichshows an illustration of an ultrasound device of the present inventioncomprising an acoustic hyperlens. Systems, methods and devices forproviding ultrasound for the present invention may comprise materialsthat bend light or sound and can focus the waves. Such materials havebeen used to make hyperlenses, also referred to as superlenses ormetamaterials. Such materials, superlenses and other similar componentsmay be used to focus the ultrasound waves in the methods and devices ofthe present invention. For example, transducers, of any type, inconjunction with a focusing element such as a hyperlens or metamaterialare used for focusing the ultrasound waves used to modulate brainactivity. Such materials can refract light backward, or have a negativeindex of refraction. Acoustic metamaterials can manipulate sound wavesin many ways, including but not limited to, collimation, focusing,cloaking, sonic screening and extraordinary transmission. An example ofa hyperlens comprises a non-resonant radially symmetric layeredstructure as taught in Li, et al., Nature Materials, DOI:10:1038,NMAT2561, p. 1-4, 25 Oct. 2009, herein incorporated in its entirety.

As used herein, a device of the present invention capable of deliveringultrasound to a human or animal subject may be referred to as anultrasound device or as a Brain Regulation Interface (BRI), and suchterms are used interchangeably. In general, an ultrasound device may beworn on the head of a subject and the device comprises at least oneultrasound transducer for providing ultrasound waves to a portion of thebrain of the subject. The methods of providing ultrasound herein may beused on exposed brain tissue, with allowance for the effect removal ofthe skull would have on the ultrasound amount provided.

A device of the present invention comprises a structure that isacoustically connected with a subject's body, such as a head, that maybe removably attached or adjacent to the body part. In someemobodiments, transducer can be coupled to the skin of appendages suchas the hands or feet using air- or water-matched transducers tostimulate various somatosensory experiences processed by the nervoussystem including the brain. The structure may comprise elements forproviding ultrasound, an ultrasound transducer, including but notlimited to, ultrasonic emitters, transducers or piezoelectrictransducers, piezocomposite transducers, piezopolymers, and CMUTs.

A device of the present invention comprises at least a body and one or aplurality of components for generating ultrasound waves. The body of adevice may be a chassis that is insertable into other head gear, or abody may be head gear such as a cap, a headband, a helmet, a protectivehead covering, a hood, a stretchable material, a flexible materialsimilar to a scarf that can be tied on the head, or other head gear thatmay be adapted to hold components for generating sound waves and/orother components. For simplicity, the body of a device is referred toherein as a chassis or as a helmet, but that reference is not meant tobe a limitation of the invention. A chassis generally refers to a bodyof a device that can be physically combined with other head gear.Methods of the present invention may comprise use of ultrasoundtransducers or other components that are affixed to the head of thesubject, such as bolted to the skull bone and under the skin of thescalp, to provide ultrasound waveforms to the brain. One or more, orall, of the components of a device may be held within the body of thedevice, affixed to the skull or scalp of the subject, or provided in aseparate element. The separate element may be provided between the bodyand the head of the subject or may be exterior to the body of thedevice.

A device of the present invention comprises a device that is wearable bya subject and used for providing at least ultrasound waves to the brainof the subject, comprising a body which covers at least a portion of asubject's head and/or scalp, when worn by the subject, and a pluralityof components, wherein at least one component is an ultrasoundcomponent. Head as used herein comprises the region from the top of theshoulder blades, including the neck region and at least the last twovertebrae of the top of the spine, the skull and jaw bones, the ears,and the tissues residing on and within, particularly the brain. Thescalp is included within this region and refers to the area of the headwhere hair grows or where hair can be found in persons who are not bald,not including facial hair. When scalp is referred to, it refers to theregion of the head from the forehead, behind the ears, and to thehairline dorsal to the face.

FIG. 1A is a diagram that illustrates an exemplary system for modulatingbrain activity, according to an embodiment wherein the device comprisesa helmet or head covering to be worn on the head of a subject. It iscontemplated that the helmet portion is attached to the head byattachment components such as a chin strap or other components used tohold a helmet or hat on a head. It is contemplated that the device isnot connected by wires to an external source, though such embodimentsmay be employed if necessary, for example, for downloading information,or charging a mobile energy source, or providing energy to a device.

To illustrate the operation of a system and device of the presentinvention, a head is depicted wearing an ultrasound device of thepresent invention. However, the system or device does not include thehead or its external surface. A system or device comprises componentsfor generating ultrasound waves such as ultrasound transducers, of whichseveral are shown, and controller, not shown. The controller may bewithin the helmet portion, or located at a separate site on thesubject's body, or may be located at a separate site on or within thesubject's body, such surgically implanted controllers, or carried in apack or pocket, or may be remote and not attached, to the subject'sbody. A controller may be built into a transducer. A controller mayprovide drive voltages and pulse patterns to one or more transducers, ormay receive information from a remote or local component and using thatinformation, drive one or more transducers. In some aspects, thetransducer may be an emitting transducer, a receiving and transmittingtransducer, or a receiving transducer. The ultrasound transducers areconnected to a controller for receiving waveform and power, and thetransducers are driven by the controller. The transducers areacoustically coupled to the brain in order to introduce acoustic energyinto the brain. For example, acoustic coupling may be accomplished usingair, water, gel or other acoustic transmitting substrates. Suchsubstrates may be incorporated into ultrasound transducers, or may beprovided in separate containers provided between a transducer and thescalp of a subject, or may be applied directed to the scalp of thesubject, such as by applying a gel directly to the scalp of a subject.Transducers may be coupled to body parts other than the head in order toprovide stimulation of somatosensory experiences, which are processed bythe nervous system including the brain. Although applied peripherally,ultrasound transducers coupled to the body for providing somatosensoryexperiences such as pain, mechanical sensation, and thermal sensationswill modify the activity of the brain in certain circuits. Suchembodiments and devices are therefore collectively referred to as brainregulation interfaces although coupling of transducers may occur onperipheral tissues. The transducers use the received waveform and powerto emit ultrasound frequency acoustic beams or waves, such as thoseshown as wavy lines entering the brain of the subject in the figures.The controller may comprise a process for waveform formation, whichdetermines the waveform to be emitted by transducers into the brain. Forexample, a controller may comprise an electrical circuit for providingdrive voltages to a piezoelectric transducer so the transducer candeliver ultrasound waveforms to the brain. In some aspects, thetransducers are battery powered and receive only waveform informationfrom the controller.

Although a particular number of transducers and controllers are depictedin FIG. 1 for purposes of illustration, in other aspects, more or feweror the same number of transducers is included, and a controller may bereplaced by one or more devices that each perform a different orredundant function of a controller, including the waveform formationprocess. Controllers and transducers may operate independently of oneanother or may operate in conjunction with each other such as in aphased array design. Connections between transducers and a controller tosend power and waveforms to transducers may be wired, or in otherembodiments, one or more connections may be wireless, or carry power orwaveforms for multiple transducers.

Transducers may each transmit an acoustic beam into the brain, and someof the beams may intersect. In some aspects, the waveform transmitted ina beam is effective in modulating brain activity everywhere the beamintersects the neural tissue. In some aspects, the waveform transmittedin a beam is only effective, or is more effective, in an intersectionregion with another beam. In some aspects, the transmitted waveforms areeffective in only a portion of the intersection region, dependent uponinterference patterns of constructive and destructive interference amongthe waveforms in the intersecting beams. In some aspects two or moreultrasound beams may intersect with one another or with other materialssuch as metamaterials outside of the brain to create structuredultrasound patterns, which are then transmitted into the brain toactivate or inhibit one or more regions of the brain.

The intensity of the acoustic beam is given by the amount of energy thatimpinges on a plane perpendicular to the beam per unit time divided bythe area of the beam on the plane, and is given in energy per unit timeper unit area, i.e., the power density per unit area, e.g., Watts persquare centimeter (W/cm²). This is the spatial-peak temporal-averageintensity (Ispta); and is used routinely for intensity herein. Inaspects, the Ispta at the site of the brain tissue is less than 500mW/cm². In aspects of the invention, the Ispta at the site of braintissue is less than 100 W/cm². Another definition of intensity widelyused in the art is spatial-peak pulse-average intensity (Isppa); formultiple cycle pulses, the Isppa may be less than 10 W/cm².

Any ultrasound transducer known in the art may be incorporated into thehelmet component of the device or bolted to the skull of a subject andused to transmit an acoustic beam into a brain. For example, OlympusNDT/Panametrics 0.5 MHz center frequency transducers, as well as Ultran0.5 and 0.35 MHz center frequency transducers may be used in devices ofthe present invention. An ultrasound transducer may be composed of anysingle or combination of piezoelectric materials known to those skilledin the art, which include piezeopolymers, piezoceramics,piezocomposites, or any other piezoelectric material which responds to avoltage. In some aspects, capacitive micro-machined ultrasonictransducer (CMUT) technology may be used. For example, CMUTs may bearranged in flexible array designs that comfortably permit adaptive beamforming and focusing. For example, the CMUTs may be mounted on the innersurface of the helmet region to transmit ultrasound to the brain. CMUTsmay be mounted within the helmet material or on the exterior of thehelmet to transmit ultrasound to various brain regions. In an aspect,CMUTs may be mounted directly to the skull of the subject through theskin surface or underneath the skin surface to transmit ultrasoundwaveforms to the brain. In an aspect other piezoelectric materials couldbe used in place of CMUTs in a similar manner. For example, PVDF orpiezocomposites or other piezopolymers could be mounted directly to theskull of a subject through the skin or underneath the skin surface totransmit ultrasound waveforms to the brain. In some aspects, PVDF,piezocomposites or piezopolymers may be arranged in flexible arraydesigns that comfortably permit adaptive beam forming and focusing. Anaspect of the invention comprises use of ultrasound transducers or othercomponents in a device of the present invention used in combination withultrasound transducers or other components that are physically attachedto a subject, wherein both the device components and the physicallyattached components are used to provide methods for brain activitymodulation.

Any devices known in the art may be used as a controller ormicrocontroller. For example, waveforms may be generated using anAgilent 33220A function generator (Agilent Technologies, Inc., SantaClara, Calif., USA) and amplified using an ENI 240L RF amplifier. Pulsesin some waveforms may be triggered using a second Agilent 33220Afunction generator. Data controlling the above devices may be generatedby waveform formation processes using a general purpose computer withsoftware instructions. Although a system or device is depicted withseveral transducers and corresponding beams, more or fewer transducersor beams or both may be included in a system or device to produce thedesired effect.

FIG. 1B-E illustrate arrangements of transducers in exemplaryembodiments of the present invention. FIG. 1B shows a cross-section ofan ultrasound device of the present invention with the transducersplaced throughout the helmet component. FIG. 1C shows a chassis-typeembodiment which may be removably mounted within head gear such as aprotective helmet. Examples of helmet components include militaryantiballistic helmets, fireman helmets, astronaut helmets, bicyclehelmets, sports protective helmets, and fighter pilot helmets. Thechassis comprises transducers affixed to the chassis body and mayfurther comprise components for attaching the chassis to a helmet, suchas mounting straps, and a suspension system. The chassis can then beinserted into a helmet and worn by a subject so that ultrasound can beapplied to the brain of the subject. The chassis can then be removedfrom the helmet and placed in the same or a different helmet. FIG. 1Dand E show the insertion of the chassis in a helmet and the helmet withthe chassis on a subject, respectively.

Systems and devices of the present invention may comprise componentsother than those for providing ultrasound, and which may be referred toherein collectively as other components. For example, light waves orelectromagnetic energy may be provided to a brain using devices of thepresent invention. FIG. 2 shows an exemplary embodiment of an ultrasounddevice of the present invention comprising other components, such ascomponents that provide electromagnetic energy, to the brain.

Such a device may be used for stimulating or inhibiting the activity ofthe brain using magnetic radiation or for making ultrasound waves moreor less effective at changing brain activity by delivering magneticenergy prior to ultrasound waves, or after ultrasound waves, orsimultaneously during the delivery of ultrasound waves.

FIG. 4 illustrates various other components that a device may comprise.Information may be sent to or from an ultrasound device of the presentinvention and processors or microprocessors and microcontrollers,computer interfacing components, computers and software may beimplemented in the transfer of such information. A device of the presentinvention may comprise components for measuring or detectingphysiological status indicators such as heart rate, blood pressure,blood oxygenation levels such as the oxygen content of hemoglobin,hormone levels, or brain activity by detection methods, including butnot limited to, EEG, MEG, IR lasers and PAT, or fNIRS. A device of thepresent invention may comprise components for geographical or globallocation, such as GPS, or other navigational detection of the locationof the device, and its wearer. Information and commands may betransmitted to and from a remote command center, such as a centralizedcomputing cluster, wherein the remote command center can control one ormore of the other components comprised by the device. Information andcommands may be transmitted to and from a portable remote command centerthat comprises a screen or other informational device, such as a PDA ora cell phone, that the subject can access and thus control thecomponents of the device. Communication may be made with devices andcontrollers onboard or remotely located using methods known in the art,including but not limited to, RF, WIFI, WiMax, Bluetooth, UHF/VHF, GSM,CDMA, LAN, WAN, or TCP/IP. FIG. 5 illustrates a device comprisingcomponents including ultrasound transducers,microprocessors/microcontroller, a COM device for transmittinginformation and control to and from a remote command center, all ofwhich are contained by the helmet portion, the body, of the device.

FIG. 6 illustrates an exemplary ultrasound device comprising locationalor global positioning components. For example, the microprocessorreceives information from a GPS unit. The GPS data may be processed by amicroprocessor integrated in an ultrasound device. This information isused to activate the ultrasound transducer to generate ultrasound tostimulate a brain structure, for example, one or more sections of thevestibular system and/or to modify the vestibular ocular reflex. Thisaids in the navigation of the user, for example by causing a change inthe subject wearer's body orientation or position. The GPS component ofthe ultrasound device can be used for locating, tracking and providingnavigational support to the subject wearing the device and to remotecommand centers. The GPS component may be used to locate or track asubject wearing the device.

FIG. 7 illustrates an exemplary device having movable or rotatablecomponents, such as a movable or rotatable ultrasound transducer. Theultrasound fields may be adjusted manually or automatically, eitherlocally or remotely controlled, by using transducers mounted on a 1-,2-, 3-spatial axis motion controller. The direction of the ultrasoundtransmitted into the brain may be modified, focused or provide asweeping action of ultrasound waves to the brain. A signal may be sentto a motion controller to change the position of the mounted transducerone or more times, or may provide a constant movement (sweeping) for thetransducer. FIG. 7 also illustrates other components such as a sensorfor brain activity.

The present invention comprises systems for modulating activity in abrain structure. For example, a system for modulating activity in abrain structure may comprise a support for at least one ultrasoundtransducer, at least one ultrasound transducer; and an instruction forat least one ultrasound component. For example, a support may be a bodyor an element that contains components such as an ultrasound transducer.An instruction may comprise commands from a microprocessor ormicrocontroller driving the ultrasound transducer to provide ultrasoundwaves at a desired frequency, intensity or waveform.

Systems and devices for providing ultrasound for the present inventionmay comprise helmets having materials that bend light or sound and canfocus the waves. Such materials, including but not limited to,super-lenses, hyperlenses or metamaterials, and other similar componentsmay be used to focus the ultrasound waves in the methods and devices ofthe present invention. For example, transducers, of any type, inconjunction with a focusing element, such as a acoustic hyperlens,super-lens or metamaterial, are used for focusing the ultrasound wavesbelow the diffraction limits and are provided to one or more sites inthe brain to modulate brain activity. Such materials can refract lightor sound backward, or have a negative index of refraction and have beenreferred to as a “metamaterial”. A focusing element, such as ametamaterial, may be used in conjunction with one or more transducers,and/or with phased arrays of transducers in order to focus or directultrasound waves to one or more brain regions.

Ultrasound devices of the present invention may be constructed ofdifferent materials depending on the intended application. For example,in some aspects where the ultrasound device comprises a personalprotection helmet, the materials used in the construction of suchhelmets may include molded polycarbonate plastics (i.e. GE Lexan),carbon fiber composites, and/or ABS plastics. In other aspects, theultrasound devices may comprise anti-ballistic helmets for combat,tactical, military, and/or national security personnel. Materials usedin the construction of such helmets may include thermocomposite plastics(hybrid thermoplastics) reinforced with carbon fibers, DuPont Kevlar,DuPont Mark Ill, Honeywell Spectra, DSM Dyneema, aramid/polyvinylbutyral phenolic combinations, thermoplastic polyurethane, polyphenylenesulfide, polypropylene, and/or polyethylene. In aspects where ultrasounddevices are used for medical intervention or treatment, the head gearportion may be constructed of any plastic or composite materials, andmay be made of or include metals such as aluminum, titanium, steel, andceramic-metal composites. Aspects of ultrasound devices, for example,one used in methods comprising video-gaming/entertainment,aircraft/space helmets, and/or communication applications, may beconstructed using any suitable material. Devices may comprise othermaterials such as natural and/or synthetic raw materials such as, butnot limited to nylon, vinyl, leather, platinum, copper, silver, gold,zinc, nickel, and polymer-based plastics such as Delrin. Ultrasounddevices of the present invention may also comprise light-emitting diodes(LEDs), organic light-emitting diodes (OLEDs), laser-diodes, magneticcoils, and/or epoxies depending on the embodiment and intended use of anultrasound device. Materials and methods of constructing head gear suchas helmets are known to those skilled in the art.

The present invention comprises devices and methods for treating oralleviating traumatic brain injury (TBI), which may be referred toherein as brain trauma. TBI may result from one or several activitiesthat can cause TBI such as combat injury, trauma to the brain fromsports or trauma resulting from accidents such as car crashes or falls.While some brain injuries have immediate and obvious physical effects,some TBI events associated with mild concussions stemming from combat orblast injury or sport-related injuries may be mild at first, but developover time. Following the initial brain insult, secondary damage mayspread throughout the brain and can lead to severe mental, cognitive,sensory, emotional and physical impairments arising from cell death,excitotoxicity, and other events occurring from the secondary injury.The secondary injury may last from hours to days to months following theprimary insult.

Methods and devices of the present invention reduce the deleteriousconsequences of secondary injury following a TBI provide enhancedrecovery and minimize damage caused during delayed injuries. Methods anddevices of the present invention reduce, minimize, and/or eliminateprimary and secondary injuries stemming from TBI or other brain injuryresulting from ballistic or blast injuries in military or combatpersonnel or related civilian casualties. Devices of the presentinvention which provide ultrasound waves may be used to treat,ameliorate, reduce, minimize, and/or eliminate primary and secondaryinjuries stemming from TBI or other brain injury resulting from anaccidental head trauma such as an automobile, bicycle or skateboardaccidents, sport-related concussive injury, such as those commonly foundin American Football, lacrosse, soccer, rugby or hockey. Devices maycomprise personal protective headgear such as a helmet which is commonlyworn by military personnel or sports participants, or may be provided asa medical device to be administered by emergency personnel such as aphysician and/or EMT. Methods of the present invention comprise treatingor ameliorating the effects of trauma to the brain by providing aneffective amount of ultrasound to a brain region that has receivedtrauma or a surrounding or remote brain region that has or could havesecondary injuries from the trauma, said ultrasound may be provided byan ultrasound device of the present invention.

Devices of the present invention that are useful in treating TBI mayprovide focused and/or unfocused ultrasound having a frequency rangingfrom 25 kHz to 50 MHz and an intensity ranging from 0.025 to 250 W/cm²which may modulate brain function and provide neuroprotection byregulating cerebrovascular dynamics (vasodilation/vasoconstriction),direct modification (inhibition) of neuronal circuit (bioelectric)activity, direct excitation of neuronal circuit activity, modulating thebuffering of intracellular calcium concentrations, and/or increasing thesynthesis and/or release of neurotrophic factors such as brain-derivedneurotrophic factor. A device may be provided to the head of a subject,such as a human or animal, during the engagement of risk-relatedactivity, or provided to the subject as long as needed, for example,from 500 msec to years following the initial injury. An aspect of theinvention comprises using an ultrasound device of the present inventionin rapid response situations, such as responding to a car accident, orduring evaluation of the subject after an incident of force to the headto reduce secondary injury to the brain. In use, a device may beautomatically activated in response to an external event, such as aconcussive blow detected by a pressure/force sensor or may be activatedby the subject wearing the device or by other appropriate personnel,either in direct contact with the subject or by remote activation. Adevice may comprise a pressure/force transducer or sensor to detect aforce event impacting the head of a device wearer. The pressure/forcetransducer or sensor may communicate with a controller ormicroprocessor, either contained within the device or at a remote site,to initiate the sequence of steps needed to activate at least oneultrasound transducer to provide ultrasound to the device wearer tominimize subsequent secondary injury to the brain. A device may compriseglobal positioning capabilities, such as a GPS transceiver forcommunicating the global position of an injured subject with a deviceattached, which would aid in medical personnel locating the injuredsubject.

The present invention comprises methods for stimulating normal brainwave activity patterns in deep or superficial brain circuits usingtranscranial pulsed ultrasound. The present invention comprisesmodifying cognitive processes such as learning and memory usingtranscranial pulsed ultrasound, for example, by stimulating sharp waveripple oscillations, or activity in any other frequency band includinggamma, beta, theta, or alpha. Though not wishing to be bound by anyparticular theory, it is believed that sharp wave ripple oscillationsunderlie memory consolidation. Pulsed transcranial ultrasound methodsmay be used to modulate BDNF signaling and for example, other cellularcascades mediating processes underlying synaptic plasticity andlearning. Such methods may comprise application of ultrasound to one ormore brain regions for one or more times. Methods compriseadministration of ultrasound waves to the brain continuously, or onregular intervals, as necessary to affect the brain area and reach thedesired outcome. Such methods are disclosed herein.

The present invention comprises methods of using transcranial pulsed USto stimulate one or more intact brain circuits wherein such methods donot require exogenous factors or surgery. Due to temperature increases<0.01° C. in response to US stimulus waveforms (FIG. 5D), an aspect ofthe invention comprises predominantly nonthermal (mechanical)mechanism(s) of action. Though not wishing to be bound by any particulartheory, it is thought that the nonthermal actions of US are understoodin terms of cavitation—for example, radiation force, acoustic streaming,shock waves, and strain neuromodulation, where US producesfluid-mechanical effects on the cellular environments of neurons tomodulate their resting membrane potentials. The direct activation of ionchannels by US may also represent a mechanism of action, since many ofthe voltage-gated sodium, potassium, and calcium channels influencingneuronal excitability possess mechanically sensitive gating kinetics(Morris and Juranka, 2007). Pulsed US could also produce ephapticeffects or generate spatially inhomogeneous electric fields, proposed tounderlie aspects of synchronous activity (Anastassiou et al., 2010;Jefferys and Haas, 1982). underlying the ability of US to stimulateintact brain circuits.

Methods, systems and devices of the present invention comprise usingpulsed US to probe intrinsic characteristics of brain circuits. Forexample, US stimulation of motor cortex produced short bursts ofactivity (<100 ms) and peripheral muscle contractions, whereasstimulation of the hippocampus with similar waveforms triggeredcharacteristic rhythmic bursting (recurrent activity), which lasted 2-3s. Stimulation of a given brain region with US can mediate broadercircuit activation based on functional connectivity. Such abilities havebeen shown and discussed for other transcranial brain-stimulationapproaches like TMS (Huerta and Volpe, 2009). For example, the effectsof US on activity in corticothalamic, corticocortical, andthalamocortical pathways are contemplated by the present invention.Brain activation with transcranial pulsed US may be dependent on theplane of anesthesia. For example, when mice were in moderate to lightanesthesia planes (mild responsiveness to tail pinch), US-evokedactivity was highly consistent across multiple repeated trials.

Using a method of transcranial US brain stimulation with an acousticcollimating tube (d=2 mm), an estimate of the volume of corticalactivation may be ≈3 mm³ as indicated by c-fos activity (FIG. 15). Thisactivated brain volume may have been restricted by anatomical featuresalong the dorsal-ventral US transmission path implemented (for examplethe corpus callosum restricting the depth of activation to the cortex).The 1.5-2.0 mm lateral area of activation observed represents a morereliable measure and is approximately five times better than the ≈1 cmlateral spatial resolution offered by transcranial magnetic stimulation(TMS) (Barker, 1999). Due to the millimeter spatial resolutionsconferred by US, structured US fields may be used to drive patternedactivation in sparsely distributed brain circuits. Similarly, focusingwith acoustic meta-materials (having a negative refractive index)enables subdiffraction spatial resolutions to be achieved for US (Zhanget al., 2009). Brain regions <1.0 mm may be accurately targeted forneurostimulation using 0.5 MHz US. Such spatial scales make transcranialUS for brain stimulation amenable to a variety of research and clinicalapplications.

Focusing of US through skull bones, including those of humans, can beachieved using transducers arranged in phased arrays. A recent clinicalstudy reported using trans-cranial MRI-guided high-intensity focusedultrasound (0.65 MHz, >1000 W/cm²) to perform noninvasive thalamotomies(d=4.0 mm) for the treatment of chronic neuropathic pain by focusing USthrough the intact human skull to deep thalamic nuclei using phasedarrays (Martin et al., 2009). Pulsed US in the noninvasive stimulationof human brain circuits is contemplated by the present invention.

The present invention comprises methods wherein two modalities are usedsimultaneously or sequentially. As US is readily compatible withmagnetic resonance imaging (MRI) it is feasible that pulsed US could beused for brain-circuit stimulation during simultaneous MRI imaging inthe functional brain mapping of intact, normal or diseased brains.Aspects of methods comprise pulsed US used to induce forms of endogenousbrain plasticity as shown with TMS (Pascual-Leone et al., 1994). In suchan embodiment, pulsed US drives specific brain activity patterns shownto underlie certain cognitive processes like memory trace formation(Girardeau et al., 2009; Nakashiba et al., 2009). For example, in mice,transcranial US can promote sharp-wave ripple oscillations (FIG. 16C)and stimulate the activity of endogenous BDNF (FIG. 16D), an importantregulator of brain plasticity and hippocampal-dependent memoryconsolidation (Tyler et al., 2002).

A method of the present invention comprises blocking memory formationand memory consolidation to prevent the formation of short- and/orlong-term memories. Such methods include methods for treating,ameliorating or reducing post-traumatic stress disorder (PTSD), such asthat resulting from combat stress. Other methods include use of a deviceof the present invention in applications where it is beneficial ornecessary that the subject's memory is altered or prevented fromforming. A device may comprise an anti-ballistic helmet and/or otherhead wearable device wherein the ultrasound treatments are administeredby the subject wearing the device or by other personnel. A device mayprovide focused and/or unfocused ultrasound ranging from 25 kHz to 50MHz and an intensity ranging from 0.025 to 250 W/cm² in a treatmentmethod to modulate brain function in a manner that alters neuronalplasticity such that the formation of memories related to specificevents are blocked. Such methods may comprise prior, concurrent or posttreatment with chemical, electrical, magnetic, or genetic methods toenhance the memory control.

Methods of the present invention comprise altering synaptic plasticityby providing ultrasound to memory centers of the brain. Ultrasoundmethods are used to reduce synaptic plasticity or to promote certaintypes of synaptic plasticity such as long-term depression if a memory isto be forgotten, and synaptic plasticity such as long-term potentiationis enhanced if a memory is to be retained. Promotion of plasticity inmemory centers is useful in treatments for dementia, Alzheimer'sdisease, or loss of memory due to other events, such as a stroke. Memorycenters of the brain comprise the limbic system, the prefrontal cortex,the hippocampus, the amygdyla, the cerebellum and entorhinal cortex,including Broadman's Areas 34 and 28.

Methods of the present invention comprise impeding or inhibiting memoryformation in a subject by providing an effective amount of ultrasound toa brain region, wherein the brain region comprises the hippocampalformation, hippocampus proper, limbic system, amygdala, thalamus,cerebellum, striatum, entorhinal cortex, perirhinal cortex, and cerebralcortex (including prefrontal cortex, auditory cortex, visual cortex,somatosensory cortex, and/or motor cortex), afferents or efferents ofsaid regions, or combinations thereof. Methods of the present inventioncomprise providing ultrasound to a subject, optionally using anultrasound device described herein, prior to an event, for example,about 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour,1.5 hours, 1.75 hours, 2 hours, 2.5 hours, 2.75 hours, 3 hours, 3.5hours, 4 hours or for about 4.5 hours prior to an event for which asubject's memory is to be impeded, and optionally, providing ultrasoundto a subject during an event, and optionally after the event occurs, forexample, for at least 1 minute, 10 minutes, 20 minutes, 30 minutes, 1hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours,11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, or fora longer time period if needed, after the event, and thereby inhibitingmemory formation or storage. Methods may also comprise providingchemical, pharmaceutical, electrical, magnetic or light therapy before,during or after ultrasound is provided. A method of the presentinvention comprises providing ultrasound using a device describedherein.

Human brain targets where ultrasound is provided to prevent theformation of memories include, but are not limited to, the hippocampalformation, hippocampus proper, amygdala, thalamus, cerebellum, striatum,entorhinal cortex, perirhinal cortex, and cerebral cortex (includingprefrontal cortex, auditory cortex, visual cortex, somatosensory cortex,and/or motor cortex). Embodiments of the present invention comprise useof a device of the present invention to provide ultrasound to modifybrain activity in at least one, or in a combination of theaforementioned anatomical areas in a manner that is effective to disruptnormal neuronal plasticity including, for example, long-termpotentiation (LIP), long-term depression (LTD), spike-timing dependentplasticity (STDP), and/or homeostatic plasticity by modulating thespatiotemporal patterns of brain activity, which lead to the formationof short- and/or long-term memories. Changes in brain activity inducedby ultrasound may act on calcium-dependent biochemical processes, whichinclude an increase and/or decrease in either, or both, kinase andphosphotase activity to modulate the activity of proteins, by modulatinggene transcription, or protein translation. Conversely, differentultrasound waveforms may be projected to the aforementioned brainregions in a manner which will promote neuronal plasticity (LTP/STDP) inorder to enhance the learning and/or memory of events as a therapeutictreatment method for dementia, Alzheimer's disease or other age-related,injury-related, and/or developmental memory disorders.

Methods of the present invention comprise administration of ultrasoundto the brain of an animal, including humans, such as by transcranialroutes, to modify cognitive processes. An aspect of the inventioncomprises providing transcranial pulsed ultrasound to modify cognitiveprocesses in a human or animal. For example, spatial learning and memorycan be modified using methods of the present invention (FIGS. 17 and18A-18B). Methods of the present invention comprise delivery of pulsedtranscranial ultrasound to the intact hippocampus and/or associatedbrain regions to modify cognitive processes, including by not limitedto, modifying normal cognition or enhancing cognitive processes. Methodsfor increasing the strength of synapses comprise providing transcranialultrasound to one or more brain regions.

The Morris Water Maze is a classic test used to assay cognition inrodents. Intact mice hippocampi were stimulated using ultrasound methodsdisclosed herein. If US stimulation occurred 5 minutes immediatelybefore training the mice on the MWM task, the mice do not learn as welland additionally, the mice have worse memory of the escape locationcompared to sham controls. It is currently believed that the disruptionof learning and memory consolidation is due to stimulating hippocampalactivity in patterns absent of context, which disrupts the formations ofassociations amongst environmental cues, as well as alters the neuronalfiring code needed for normal learning and memory to occur. Thus, byproviding disruptive hippocampal stimulation with pulsed ultrasoundlearning can be attenuated and memory can be blocked. Methods of thepresent invention comprise providing ultrasound to disrupt learningand/or interfere with memory consolidation by stimulating one or morebrain regions in the absence of context (for the animal stimulated).

For example, if mice are stimulated for 5 minutes per day for 7 daysbefore training them on the MWM task (without stimulating the day of orimmediately before training on any training day) then the mice receivingintact hippocampal stimulation in this chronic paradigm perform betterthan sham controls. They remember better and learn faster. It isbelieved that traditional models of plasticity explain the findings,where the synaptic strengths of hippocampal synapses are increased bystimulating across repeated days in controlled environments. Ultrasoundstimulates the release of brain-derived neurotrophic factor (BDNF) andBDNF induces plasticity and mediates learning, thus, the repeatedprolonged increase in BDNF signaling enhances cognitive function.Methods of the present invention comprise repeated stimulation of thehippocampus by transcranial ultrasound to improve learning and memory.Methods of the present invention comprise repeated stimulation of one ormore brain regions by transcranial ultrasound to improve learning andmemory. Methods of the present invention comprise repeated stimulationof the hippocampus by transcranial ultrasound for treating a disease orphysiological condition where disrupted cognition is present in ananimal. For example, such diseases or physiological conditions include,but are not limited to, mental retardation, Down's syndrome, Fragile X,Alzheimer's disease, age-related cognitive decline, and other conditionswhere cognition is delayed, faulty or impaired. Methods comprisingproviding ultrasound to the brain of an animal for the upregulation ofneurotrophic factors may be used treat diseases where different braincircuits are targeted. For example, dysregulated BDNF signaling occursin diseases or physiological conditions including, but not limited to,epilepsy, anxiety, depression, Alzheimer's disease, Parkinson's disease,and following stroke and brain injury. Methods of the present inventioncomprise upregulation of neurotrophic factors, including but not limitedto BDNF, Nerve Growth Factor, Neurotrophin-3, Fibroblast Growth Factor,Insulin-like Growth Factor, by transcranial ultrasound for treating adisease or physiological condition where neurotrophic dysregulation orimpaired neurotrophic signaling occurs. For example, increasing BDNFsignaling by performing chronic repeated brain stimulation withultrasound may encourage plasticity which can have a profound effect ondiseased, faulty or impaired brain circuits. Likewise, chronic repeatedbrain stimulation with ultrasound may encourage plasticity to enhancelearning and memory in normal brain circuits. An ultrasonic method ofthe present invention comprises enhancing learning or memory formationin a subject, comprising providing an effective amount of ultrasound toa brain region, wherein the brain region comprises the hippocampalformation, hippocampus proper, amygdala, thalamus, cerebellum, striatum,entorhinal cortex, perirhinal cortex, and cerebral cortex, prefrontalcortex, auditory cortex, visual cortex, somatosensory cortex, or motorcortex, afferents or efferents of the regions, or combinations thereof.

Aspects of the present invention comprise methods and devices to providetranscranial ultrasound to modify dysfunctional, impaired or diseasedbrain circuits in humans and animals. Patients with various types ofbrain impairments have been shown to benefit from brain stimulationusing electromagnetic energy, such as that transduced using electrodes,lasers, magnetic coils, and other energy emitting devices. Ultrasoundfor brain stimulation can confer many advantages overelectromagnetic-based brain stimulation strategies. For example, aspectsof ultrasound methods disclosed herein do not require surgery and canconfer a spatial resolution at least 3-5 times better than that achievedwith other noninvasive techniques, such as transcranial magneticstimulation. Further, ultrasound can be rapidly deployed for brainstimulation, which can facilitate the providing of first lineinterventions to treat traumatic brain injuries or neurocritical careconditions such as refractory seizure activity.

Methods disclosed herein attenuate seizure activity using pulsedultrasound.

Brain regulation devices disclosed herein can be used in neurocriticalcare situations to rapidly provide a noninvasive brain stimulationintervention using pulsed ultrasound. For example, status epilepticus(SE) refractory to conventional anti-epileptic drugs typically has apoor prognosis, but patients may recover well if seizures can beterminated. Methods for using transcranial pulsed ultrasound (TPU) tostimulate intact brain activity are disclosed herein and can be used fortreatment of seizure activity. TPU can synchronize intact hippocampaloscillations in high-frequency and gamma bands without producing damage.Data disclosed herein shows TPU can disrupt kainic acid-induced SE byproviding a whole-brain stimulation interference source. The studiesshowed acute and chronic effects of transcranial ultrasound on healthyand kainic acid (KA) induced SE mice.

Methods of the present invention comprise treatment of brain dysfunctionby modulating cortical and subcortical brain circuit activity byproviding ultrasound to the cortical and subcortical regions of thebrain. The present invention is useful for treating neurocriticalemergencies like SE that carry high morbidity. SE-induced in rodentsserves as a model of Temporal Lobe Epilepsy with hippocampal sclerosis,the most frequent epilepsy in humans. Aspects of the present inventioncomprise treating temporal lobe epilepsy, optionally with hippocampalsclerosis, by providing ultrasound to one or more brain regions. Suchultrasound may be pulsed transcranial ultrasound.

Aspects of the methods of the present invention comprise use of pulsed,transcranial ultrasound, continuous wave ultrasound or both. Use ofultrasound devices disclosed herein may be used in methods for acutetreatment of brain diseases or impairment. Devices for providingultrasound as disclosed herein may be used treating brain diseases orbrain impairment by providing chronic stimulation. For example, chronicstimulation with brain regulation devices providing ultrasound may beused to increase plasticity and enhance cognitive processes in animalsto treat degenerative diseases such as Alzheimer's disease. Such devicesand methods may be used to treat neurodevelopmental diseases in childrenor other aged humans or animals, such as mental retardation, fragile x,Down's syndrome, etc. Both diseased or impaired brain tissues and normalbrain tissues may be modulated using ultrasound devices disclosedherein.

As shown in FIG. 19, continuous wave ultrasound, in contrast to pulsedultrasound, may be used to induce seizure activity in normal braincircuits. In diseased or impaired brain circuits, such as when seizureactivity is present, continuous wave ultrasound or pulsed ultrasound maybe used to disrupt the aberrant activity, such as seizures. The outcomeis highly dependent on the initial state of the brain. If aberrantactivity is present, methods providing ultrasound can interfere withaberrant activity. If aberrant activity is not present, such as innormal brain tissue, the induction of seizures may be used tofunctionally identify epileptic circuits. Use of ultrasound devices andmethods described herein are useful prior to, during, or after surgicalmanipulation of brain tissue, for example, to map functional and/ordysfunctional brain circuits. For example, methods comprise use ofultrasound to identify diseased brain circuits, such as epileptic braincircuits which may require surgical removal.

Aspects of the present invention comprise methods and devices to provideultrasound to regulate or modify the activity of certain brain circuitsto reduce anxiety and stress responses induced by environmental cues orother conditions, for example, combat situations or operation of complexor sensitive machinery such as a space shuttle, or otherintra-/extra-atmospheric craft. Though not wishing to be bound by anyparticular theory, it is believed that stress responses are mediated inthe brain and/or nervous system by several neuromodulators,neurohormones, and neurotransmitters including, but not limited tonoradrenaline, epinephrine, norepinephrine (NE), acetylcholine (ACh),cortisol, corticotropin-releasing hormone (CRH), adrenocorticotropichormone (ACTH), and glucocorticoids. Brain circuits involved inmediating responses to stressors include, but are not limited to, thelocus ceruleus, the paraventricular nucleus of the hypothalamus (PVN),the autonomic nervous system, the sympathetic nervous system;(“fight-or-flight” response), hypothalamic-pituitary-adrenal axis (HPA),adrenal medulla, and the pons. Methods of the present invention comprisealtering a stress response by a subject by providing an effective amountof ultrasound to a brain region, wherein the brain region comprises thelocus ceruleus, the paraventricular nucleus of the hypothalamus (PVN),the autonomic nervous system, the sympathetic nervous system;(“fight-or-flight” response), hypothalamic-pituitary-adrenal axis (HPA),adrenal medulla, or the pons.

There are several different types of stress responses. The“fight-or-flight” stress response is an acute stress response, which isput into effect when a general alarm system in the brain is activated byan increase in the activity of neurons in the locus ceruleus. Thisincrease in activity leads to an increase in noradrenergic activity toincrease awareness and attention. Other acute stress responses includethe actions of Ach to trigger the release of epinephrine and NE from themedulla and adrenal glands, as well as activation of the HPA to mediateappropriate behaviors. Acute stress can be positive for the subject insituations where the subject is challenged. Prolonged exposure to acutestress leads to decreased cognitive and physiological functioning. Thisis due to an abnormally high level of circulating stress hormones, suchas cortisol, CRH, ACTH, as well as maladaptive plasticity in local braincircuits such as the locus ceruleus, PVN, hippocampus, prefrontalcortex, and the amygdala.

Problems associated with prolonged chronic stress, such as that seen inmilitary or tactical personnel, presents major problems and is termedcombat stress reaction, which has been previously called shell shock orbattle fatigue. Combat stress reaction can manifest itself leading tofatigue, slow response times lack of ability to make decisions, lack ofan ability to carry out missions, disconnection, and other poorcognitive abilities. Combat stress reaction can lead to other stressdisorders such as post-traumatic stress disorder, generalized anxietydisorder, depression, and acute stress disorder. Subjects other thanmilitary or combat personnel can present with combat stress reaction orother stress disorders and be treated using methods described herein.

An aspect of the present invention comprises use of a device forproviding ultrasound of the present invention to decrease thedeleterious effects of prolonged stress on physiological and cognitiveperformance of a subject by providing ultrasound to excite and/orinhibit the aforementioned brain stress systems. In an aspect of theinvention, the acute stress response is left intact to maximizecombat/tactical personnel efficiency during hostile engagement, but theactivity of the brain stress centers are reduced by providing ultrasoundfollowing environmental exposure to the stressors. For example, after astressful event, such as a battle or a patrol in a dangerous region,tactical, military, or combat personnel activate the ultrasound deviceonce they have returned to a relatively safe environment. In anembodiment, a sensor that detects circulating stress hormone levelscommunicates information regarding the subject's physiological state ofstress hormones is in communication with an ultrasound device worn bythe such that the ultrasound device becomes active and provides aneffective amount of ultrasound to reduce prolonged and/or chronicstress. Reduction of the stress response interrupts the chronic state ofstress which leads to the combat stress reaction and underliessubsequent PTSD, depression, generalized anxiety disorder, and acutestress disorder in many individuals.

Methods of the present invention comprise use of an ultrasound device toprovide ultrasound to activate brain regions, which increase arousal,attention, and awareness. Methods for activation of brain regions may beemployed by any subject where arousal, attention or awareness aresought. For example, ultrasound devices may be worn by operators ofheavy machinery or equipment, astronauts, pilots, and combat or tacticalpersonnel where increased attention, arousal, increased alertness andfor long-term wakefulness is desirable in order to improve performanceand to minimize risk of injury to the user and others and/or accidents.Shift-workers or long-haul truck drivers may also benefit from suchmethods.

There are numerous centers in the brain which are responsible forregulating attention, arousal, and alertness. Increasing activity inthese brain regions can increase reaction times, enhance cognitiveperformance, and promote appropriate behavioral or physiologicalresponses. Some of the neurotransmitter and neuromodulator systemsinvolved in the regulation of arousal and alertness are acetylcholine,dopamine, histamine, hypocretin, serotonin, and norepinephrine. Braincircuits, which mediate arousal and attention include, but are notlimited to the prefrontal cortex, basal forebrain, the hypothalamus,tuberomamillary nuclei, basolateral amygdala, ventral tegmental area,medial forebrain bundle, locus ceruleus, the thalamus, and the dorsalraphe nucleus. Specific thalamocortical oscillations (˜40 Hz) are knownto occur during wakefulness or alertness and can be detected using EEGand or MEG. There are other patterns of brain activity, which indicateenhanced arousal, alertness, and attention and these can also bedetected using MEG and or EEG.

Methods of the present invention comprise activating arousal brainregions to increase alertness, awareness, attention or long-termwakefulness in a subject by providing an effective amount of ultrasoundto a brain region, wherein the brain region comprises prefrontal cortex,basal forebrain, the hypothalamus, tuberomamillary nuclei, basolateralamygdala, ventral tegmental area, medial forebrain bundle, locusceruleus, the thalamus, and the dorsal raphe nucleus. Ultrasound may beprovided by a device of the present invention. A device may providefocused and/or unfocused ultrasound ranging from 25 kHz to 50 MHz and anintensity ranging from 0.025 to 250 W/cm² in a treatment method tomodulate brain function in a manner that alters alertness, wakefulness,and/or attention. Methods of the present invention comprise providingultrasound to effect release of acetylcholine, dopamine, histamine,hypocretin, serotonin, and norepinephrine. For example, an ultrasounddevice of the present invention may provide ultrasound to a subject toactivate to activate arousal brain regions in the subject to increasealertness, awareness, attention, and long-term wakefulness for enhancedattention and alertness during sensitive operations, such as duringcombat environments, while operating heavy machinery, for astronauts, orpilots.

Methods of providing ultrasound to activate arousal brain regions may beused to promote long-term wakefulness by using ultrasound to stimulateone of more of the arousal brain regions, systems, circuits and/or forneurotransmitter release. Subjects engaged in long-term activityactivate an ultrasound device of the present invention to reduce thelikelihood of entering sleep cycles or to prevent microsleep. Methodscomprise use of an ultrasound device of the present invention incombination with EEG and/or MEG sensors to monitor brainwave activity.The sensors can relay information regarding the brainwave patterns to anonboard microprocessor or a remote processor such that when brainwavesshow the user is entering a reduced awareness/alertness or sleep cyclethe ultrasound device is activated, such as by a microcontroller, tobegin transmitting ultrasound to one or more arousal-related brainregions which increases wakefulness such that the subject returns to anawake state. Methods of providing ultrasound to activate arousal brainregions or neurotransmitters in a subject for arousal include treatingsubjects in reduced consciousness states, such as those in a coma or aminimally conscious state where thalamocortical activity andoscillations are impaired or disrupted.

A device of the present invention may comprise multiple components foractivating brain structures. For example, a device may comprise laserdiodes and MEG/EEG sensors, in addition to ultrasound transducers andoptionally magnetic transducers. Scattered photons from the laser diodesare provided at the inner surface of the body of the device so that thephotons are between the inner surface of the device and the outersurface of the head. The scattered photons are detected by ultrasoundtransducers present on the inner surface of the body of the device. Theinteraction with the photons provides information about brain activityregarding blood flow and blood oxygenation via photoacoustic tomography.In an alternative aspect, sensors that provide information about thescattered photons can be used in functional near-infrared spectroscopy(fNIRS). MEG (magnetoencepholography) or EEG sensors may be used in adevice of the present invention to detect electrical brain activity, orto detect changes in brain electrical activity. The data regarding brainactivity acquired from these sensors can be relayed to a remote or localmicroprocessor. A local microprocessor may one that is integrateddirectly in or on the body of the device. The relayed data may be usedby the microprocessor to return instructions to components in thedevice, such as ultrasound transducers, such as to modulate theultrasound waveform, adjust the frequency, intensity or waveformcharacteristics to fine tune the ultrasound being delivered to thesubject.

Methods of the present invention comprise activation of reward pathwaysin a subject by providing an effective amount of ultrasound to a brainregion, wherein the brain region comprises the mesolimbic andmesocortical pathways, including connections between the medialforebrain bundle (MFB) and its connections to the nucleus accumbens (NA)wherein dopamine (DA) acts as a neuromodulator, the prefrontal cortex,the anterior cingulate cortex (ACC), basolateral amygdaia (BLA), or theventral tegmental area (VTA), as well as dopaminergic, glutamtergic,serotonergic, and cholinergic systems. Ultrasound may be provided by anultrasound device of the present invention. Activation of rewardpathways may be used to condition and/or reinforce certain desiredattributes and/or to motivate specific behavioral actions. The majoranatomical pathways responsible for “reward” in the nervous system arethe mesolimbic and mesocortical pathways, which include connectionsbetween the medial forebrain bundle (MFB) and its connections to thenucleus accumbens (NA) wherein dopamine DA acts as a neuromodulator.Other areas crucial to reward pathways involve the prefrontal cortex,the anterior cingulate cortex (ACC), basolateral amygdaia (BLA), and theventral tegmental area (VTA). These reward (pleasure) centers of thebrain have powerful functions in reinforcing certain behaviors. Thesepathways mediate addiction to drugs of abuse and/or other appetitivebehaviors. For example, in rats conditioned to press a bar to receiveintracranial self-stimulation (ICSS) of the VTA, MFB, and/or NA willlead to reinforcing behaviors such that the rat ignores all otherenvironmental cues and will engage in repeated bar pressing behaviors inorder to gain the reinforcing/pleasure inducing ICSS of those brainnuclei.

Methods of the present invention comprise ultrasound devices thatdeliver ultrasound waveforms to any one or a combination of the rewardbrain regions in order to reinforce desired behavioral actions. A devicemay provide focused and/or unfocused ultrasound ranging from 25 kHz to50 MHz and an intensity ranging from 0.025 to 250 W/cm² in a treatmentmethod to modulate brain function in a manner that rewards behaviorsand/or increases the motivation to engage in certain behaviors. Sincetemporal contiguity of the reinforcement (brain stimulation) with thebehavioral action is needed for the activation of reward pathways topromote behaviors, timing of the delivery of ultrasound waveforms to thereward brain regions may affect the behavioral response. Betterbehavioral responses are found when the delivery of reinforcingultrasound stimulus waveforms occurs in close temporal contiguity withthe behavior to be reinforced. Ultrasound stimulus waveforms may beprovided from about one hour prior to the occurrence of the behavior tobe reinforced to about one hour following the behavioral actions to bereinforced. Longer or shorter time ranges for ultrasound provision maybe appropriate for some behaviors, or for later stages of treatment, andsuch ranges may be determined by those skilled in the art. More specificand restricted timing windows for providing ultrasound may lead to morerobust behavioral conditioning. The activation of the ultrasound deviceof the present invention may be controlled by the subject or may beremotely controlled via various communication ports.

Methods for activation of reward pathways can be used for training adesired behavior or response. For example, ultrasound devices of thepresent invention may be used to provide ultrasound to a reward pathwayto reinforce behaviors that are beneficial for military/combat/tacticalpersonnel, machine operators, systems engineers, or other technicalpersonnel to train the subjects to respond with specific behavioralroutines and/or sensitive procedures. This will reduce job-specificlearning curves and to increase job-performance. Such training can alsobe used to train athletes or any other subject where conditionedresponses would be beneficial. Such training may also be used to changedeleterious behaviors by providing reward stimulation that substitutesfor the deleterious behavior. For example, when tempted to engage in adeleterious behavior such as an addictive behavior, a reward pathway isactivated and the subject is “distracted” from the deleterious behavior.

Methods of the present invention comprise providing ultrasound to theprefrontal cortex and a device of the present invention may be used toprovide the ultrasound. Providing ultrasound to the prefrontal cortex,alone or in combination with other treatments, such as transcranialmagnetic stimulation, may be used to activate that brain region and maybe useful for treatments of drug-resistant depression or clinicaldepression. Such ultrasound may be focused or unfocused.

Methods of the present invention comprise modulating cerebrovasculardynamics by providing ultrasound to brain regions. Ultrasound inducesvasodilation or vasoconstriction in peripheral tissues by activatingnitric oxide/nitric oxide synthetase. Data of the inventor showed thatair-coupled ultrasound transducers induced vasodilation in the brains ofrodents. Pulsed ultrasound remotely modulated brain hemodynamics byinducing cerebrovascular vasodilation in an intact brain. An ultrasounddevice of the present invention may alter brain activity by alteringcerebrovascular blood flow and indirectly increase or decrease neuronalactivity, altering energy utilization and metabolism, or increase oxygento brain regions. The application of ultrasound through treatmentdevices may be used to regulate the cerebrovascular dynamics of thebrain such that the blood-brain barrier is modified in order to allowthe better absorption of one or more active agents, such as drugs orpharmaceuticals, to specific brain regions, for example, so that theactive agent is effective in local brain regions while not affectingother surrounding brain regions. Application of ultrasound waves to abrain region can increase and or decrease linear blood cell density aswell as cerebrovascular flux. The modulation of blood flow can becoupled to brain activity, but it can also be uncoupled from the effectson brain activity. Methods of the present invention comprise modulatingblood vessel diameter in the brain of a human or animal, comprisingproviding an effective amount of ultrasound, in pulsed or continuousform, to a brain region, wherein an effective amount of ultrasoundcauses vasodilation or vasoconstriction of blood vessels in the area ofthe brain where the ultrasound waves impinge.

Methods of the present invention comprise activating sensory or motorbrain regions in a subject by providing an effective amount ofultrasound to a brain region, wherein the brain region comprises all orpart of a vestibular system, an aural region, a visual region, anolfactory region, a proprioperceptive region, afferents or efferents ofone or more regions, or combinations thereof. Ultrasound may be providedby an ultrasound device of the present invention. An aspect of thepresent invention comprises methods and devices that allow ahuman-machine interface for communications with the subject operablyattached to an ultrasound device of the present invention to activatesensory or motor brain regions of the subject to produce movement or tocreate synthetic brain imagery. For example, such methods and devicesare used for projections of virtual sounds to auditory regions of thebrain, ability to generate virtual maps/images onto visual brainregions, ability to control body movement patterns of an individual.Such brain stimulation may be effected either directly or indirectly.For example, an operator or the subject may stimulate the vestibularsystem to cause the subject to make a turning motion in order to guidethat subject via GPS or other feedback from navigation technology, orstimulate motor areas of the subject's brain to cause the subject tomake a motor action. Such methods and devices may be used for anyapplication, including but not limited to, recreational, entertainment,and/or video gaming applications.

Methods of the present invention comprise harvesting energy, forexample, to power a device of the present invention. For example,mechanical energy generated by a physical activity such as walking,jogging, running, peddling, etc. is converted to electrical energy usingpiezopolymers or piezoelectric fiber composites. The electrical energyproduced charges or re-charges the capacitive or battery elements whichmay be powering the ultrasound transducer microcontrollers or othercomponents of a device. For example, a subject's footwear, i.e., boot,shoe, etc. comprises PVDF piezopolymers or piezoelectric fibercomposites (e.g., Piezoflex from Airmar Technology Corp.). The subject'sfootwear may comprise one or more microcontrollers for harvesting theenergy that is generated during the physical activity. The electricalenergy then supplies power to a device via at least one microcontrollerand at least one battery. Voltage traces confirm energy harvesting orconversion of mechanical energy into electrical energy usingpiezopolymers. FIG. 9A and B are graphs showing the energy produced inthe conversion of mechanical energy to electrical energy usingpiezopolymers.

Methods of the present invention comprise methods of facilitating uni-and bi-directional communication between a subject wearing an ultrasounddevice of the present invention and a remote control unit or processor.The remote control unit/processor includes but is not limited to acentral command location or unit, or its equivalents, a monitoringstation for vital functions, or its equivalents, or some type of console(e.g., gaming console). A device of the present invention may sendinformation or data to a remote control unit/processor for furtheranalysis and evaluation, using communication networks, including but notlimited to, radio frequency (RF), wi-fi, wi-max, Bluetooth, ultrasound,and infrared radiation. Such data include but are not limited toinformation related to the subject's brain activity, vital functionssuch as EEG and MEG, and the subject's global positioning. Other datainclude photoacoustic tomography, information regarding the timing ofevents, and force/blast information. Software and algorithms may be usedto analyze the data transmitted from the subject. Based on thecomputational analysis of the data, a device may alter one or morestimuli, such as ultrasound, being provided to the subject, for example,provide modified ultrasound waveform patterns. Modifications may includechanges in acoustic frequency and intensity and changes in ultrasoundfocusing. The changes in ultrasound waveform patterns modify brainfunction to achieve a desired outcome

The disclosed methods and devices achieve acoustic impedance matchingbetween water-matched ultrasound transducers and the surface of the headof the subject. For example, one or more water-matched ultrasoundtransducers are coupled to ultrasound coupling pads and installed intoan ultrasound device. The water-matched ultrasound transducer receivesvoltage pulses from at least one microcontroller of an ultrasounddevice. For example, the ultrasound transducer is in electricalcommunication with a microcontroller at one position of the transducer,and contacts an ultrasound coupling pad at a different location of thetransducer. The ultrasound coupling pad is in contact with thetransducer in one location and, in another location of the pad, is incontact with the surface of the head of the wearer of the device. Forexample, the transducer transits from the outside of the body of thedevice to the inner surface of the device. At the outer surface of thebody of the device, the transducer is operably connected to amicrocontroller, either remotely or by an electrical means such as awire. At the inner surface of the body of the device, the transducer isin contact with the ultrasound coupling pad. The use of ultrasoundcoupling pads helps provide optimal power transfer during ultrasoundtransmission. Ultrasound coupling pads include but are not limited todegassed water in a polymer bladder. One or more ultrasound couplingpads mounted within an ultrasound device serve to couple water-matchedultrasound transducers directly to the subject's head surface.

The methods of providing ultrasound waves to neural tissue or the brainto modulate brain activity may further comprise providing other elementsor treatments, such as providing pharmaceutical or chemical compounds,and/or electrical or light waves in conjunction with ultrasound waves.Such other elements or treatments may be provided to a subject before,concurrently with, or after ultrasound is provided to the subject.Methods comprising combinations of one or more types of treatments orelements, for example, such as ultrasound and pharmaceutical treatments,are contemplated by the present invention.

Definitions

As used in the specification and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a pharmaceuticalcarrier” includes mixtures of two or more such carriers, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms another embodiment. Itwill be further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed that“less than or equal to” the value, “greater than or equal to the value”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed the “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that thethroughout the application, data is provided in a number of differentformats, and that this data, represents endpoints and starting points,and ranges for any combination of the data points. For example, if aparticular data point “10” and a particular data point 15 are disclosed,it is understood that greater than, greater than or equal to, less than,less than or equal to, and equal to 10 and 15 are considered disclosedas well as between 10 and 15. It is also understood that each unitbetween two particular units are also disclosed. For example, if 10 and15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

The term “treating” refers to inhibiting, preventing, curing, reversing,attenuating, alleviating, minimizing, suppressing or halting thedeleterious effects of a disease and/or causing the reduction,remission, or regression of a disease. Those of skill in the art willunderstand that various methodologies and assays can be used to assessthe development of a disease, and similarly, various methodologies andassays may be used to assess the reduction, remission or regression ofthe disease.

“Increase” is defined throughout as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18 ,19, 20 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50 51, 52 ,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,150, 200, 250, 300, 400, or 500 times increase as compared with basallevels or a control.

EXAMPLES Example 1

Treatment of TBI

A person is injured and has traumatic brain injury resulting fromexposure to a blast from an explosion. Because this person is a militaryservice member, the person is wearing an anti-ballistic helmetcomprising ultrasound transducers. The ultrasound transducers arelocated in a phased array or as single transducer elements. A sensor inthe helmet registers the pressure force of the blast and communicateswirelessly to a remote control position located a distance from theblast zone that a blast has occurred. A GPS signal is sent that providesdata about the location of device. A sensor, located in the attachmentstraps of the helmet, relays data that the device is still attached tothe subject. Other sensors relay data about the subject's physicalcondition such as heart rate, brain activity, blood pressure, etc. TheEEG data shows a location of injury to the brain that indicatestraumatic brain injury. In some embodiments, treatment may be providedby way of transducers that are not comprised in an anti-ballistichelmet, but through a portable treatment unit that can be administeredby emergency responding personnel such as a combat medic. Such aportable treatment unit may be comprised of one or more ultrasoundtransducers and can be handheld or not. A portable treatment unit mayalso comprise EEG electrodes in order to monitor brain activity.

Upon receiving the data, the remote site responds by transmitting dataand ultrasound wave process data to the transducers in the phased arrayof the helmet. A microcontroller changes the orientation of some of thetransducers in and adjacent to the phased array. The ultrasoundtransducers provide a focused ultrasound treatment to the site oftraumatic brain injury, comprising providing ultrasound waves at 0.5 MHzand 100 mW/cm². The ultrasound transducers also provide focused andunfocused ultrasound waves ranging from 25 kHz to 50 MHz to areas aroundthe injury site to ameliorate secondary effects from the traumatic braininjury. Medical personnel are sent to the blast site and the subjectusing GPS locational data. While undergoing ultrasound treatment, thesubject is transported to a hospital.

Example 2

Alteration of Memory

A human with post-traumatic stress disorder (PTSD), such as thatresulting from combat stress, presents to a psychiatrist requestingrelief from disturbing memories. An ultrasound device of the presentinvention is placed on the human subject's head and unfocused ultrasoundranging from 25 kHz to 50 MHz is applied in multiple treatments tomodulate brain function in a manner that alters neuronal plasticity suchthat the formation of memories related to specific events are blocked.Concurrently with ultrasound therapy, the subject is administeredanti-anxiety medication, a serotonin release inhibitor, SRI. Theultrasound waves target one or more brain regions, comprising thehippocampal formation, hippocampus proper, limbic system, amygdala,thalamus, cerebellum, striatum, etorhinal cortex, perirhinal cortex, andcerebral cortex (including prefrontal cortex, auditory cortex, visualcortex, somatosensory cortex, and/or motor cortex), brain afferents orbrain efferents of said regions, or combinations thereof. One treatmentcomprises providing ultrasound waves at 30 MHz and 300 mW/cm² to theamygdala in multiples of 250 milliseconds with a rest period of 500milliseconds for 10 minutes, evoking the memory by recall of the events,and repeating the treatment when the memory is evoked. In othertreatments ultrasound ranging in single or multiple frequencies rangingfrom 25 kHz to 50 MHz can be used to treat the brain in a pulsed orcontinuous wave mode at intensities less than 1 W/cm² in single ormultiple repeat sessions as needed. After several days to weeks oftreatment, the subject reports less depression, fewer panic attacks, andis able to return to many every day activities such as socializing withfriends.

Example 3

Reduction of Anxiety

A person is being trained to operate a space craft and a reduction instress responses is sought in performing emergency response training.While training in performing specific emergency response activities, theperson wears an ultrasound device comprising an astronaut helmet andultrasound transducers. Ultrasound waves are provided to the person'sbrain to modulate one or more of noradrenaline, epinephrine,norepinephrine (NE), acetylcholine (ACh), cortisol,corticotropin-releasing hormone (CRH), adrenocorticotropic hormone(ACTH), or glucocorticoids, and brain structures including the locusceruleus, the paraventricular nucleus of the hypothalamus (PVN), theautonomic nervous system, the sympathetic nervous system;(“fight-or-flight” response), hypothalamic-pituitary-adrenal axis (HPA),adrenal medulla, and the pons. For example, one treatment comprisesproviding unfocused ultrasound waves at 50 MHz and 40 mW/cm² by sweepingthe hypothalamic-pituitary-adrenal axis (HPA), and providing focusedultrasound waves through an acoustic hyperlens to the pons at 200 kHzand 40 W/cm². After several training sessions during which ultrasoundtreatments are provided, the stress response, as measured byphysiological data such as respiration rate, heart rate and bloodpressure, and by levels of adrenalin, is lowered in the person.

Example 4

Activation of Brain Regions for Arousal and Attention

A pilot flying airline routes from New York to Tokyo wears an ultrasounddevice of the present invention. The body of the device is formed sothat a phased array of ultrasound transducers is positioned to provideultrasound waves to the prefrontal cortex, basal forebrain, thehypothalamus, tuberomamillary nuclei, basolateral amygdala, ventraltegmental area, medial forebrain bundle, locus ceruleus, the thalamus,and the dorsal raphe nucleus. A sensor in the device, for example, anMEG or EEG sensor can detect specific thalamocortical oscillations (˜40Hz) known to occur during wakefulness or alertness. When the MEG or EEGsensor detects fewer thalamocortical oscillations or other frequencyband oscillations that indicate lessened wakefulness, the sensor dataactivates a controller imbedded in the device body to activate theultrasound array to provide unfocused ultrasound waves from about 100kHz to about 2.5 MHz in a sweeping frequency arrangement and anintensity of 250 mW/cm² to the hypothalamus, basolateral amygdala,medial forebrain bundle, locus ceruleus, the thalamus, and the dorsalraphe nucleus. The pilot is restored to a wakeful state and continues tofly the airplane in an alert condition.

Example 5

Reward Behaviors

A person has road rage attacks and experiences a road rage attack everyday while driving to work. In treatment of this condition, the personbegins wearing an ultrasound device of the present invention. When theperson controls the rage response successfully, the person thenactivates the ultrasound device to provide ultrasound waves to a brainregion for reward pathways, such as the mesolimbic and mesocorticalpathways, including connections between the medial forebrain bundle(MFB) and its connections to the nucleus accumbens (NA) wherein dopamineDA acts as a neuromodulator, the prefrontal cortex, the anteriorcingulate cortex (ACC), basolateral amygdala (BLA), or the ventraltegmental area (VTA), as well as depaminergic, glutamtergic,serotonergic, and cholinergic systems to gain the reinforcing/pleasureinducing ICSS of those brain nuclei. Ultrasounds waves at 200 kHz and300 mW/cm² are provided in 100 millisecond pulses for 3 minutes. Acooling unit is provided in the device that also functions as anultrasound coupling pad to aid in transmission of the ultrasound waves.Occasionally when tempted to engage in the deleterious road ragebehavior, a reward pathway is activated and the subject is distractedfrom the road rage.

Example 6

Virtual Applications and Peripheral and Cranial Nerves

A device of the present invention is used to provide a virtualexperience to a person by providing ultrasound waves that modulate brainactivity in the vestibular system, aural region, and a visual region.The subject wears an ultrasound device of the present invention thatprovides ultrasound waves in a focused manner from about 100 kHz to 10MHz while the virtual experience is desired. The subject may visuallyfollows a display unit of a computer running software that provides thevisual cues of the experience, for example a training exercise or avideo game. The subject responds with movements or the sensation ofmovement, hears sounds and/or sees aspects of the training program whenthe ultrasound waves are impinging on the brain regions or theperiphery. In an embodiment, ultrasound may be delivered to thevestibular nerve or the vestibular system to alter the sensation ofbalance. The modulation of the sense of balance can be coupled to avisual display during the virtual experience such that the subjectexperiences motion or the sense of movement.

In an embodiment, a device of the present invention is used to providesomatosensory feedback to the hands or feet of the subject by deliveringpulsed or continuous wave ultrasound to the periphery. In such anembodiment the ultrasound can be delivered to at least one hand by aglove or other handheld device such as a videogame controller,cellular/mobile telephone or PDA, or to a foot by a shoe, or videogamecontroller, cellular/mobile telephone or PDA. The pulsed or continuouswave ultrasound can be delivered at acoustic frequencies ranging from 25kHz to 50 MHz at intensities ranging from 30 mW/cm² to 1 W/cm² from air-or water-matched transducers arranged as single elements or phasedarrays to produce painful, mechanical, or thermal sensations inperipheral body structures, separate from the brain, such thatinteractive experiences can be modulated. In such an embodiment,stimulation of peripheral nerve structures with pulsed or continuouswave ultrasound will modulate somatosensory experiences by modulatingbrain activity through direct peripheral nerve stimulation in the hands,feet, or other body part. See FIG. 20 wherein an embodiment of anultrasound device for stimulating peripheral nerves in the hand isshown. The stimulation of the peripheral nerve will providesomatosensory feedback to the subject by changing brain activity inareas of the brain responsible for processing pain, mechanical, orthermal stimuli such as the somatosensory cortex. The materials for thetransducers can be piezoceramics, piezopolymers, gas matrixpiezoelectric transducers, or CMUTs. These devices can also be used tocharacterize peripheral nerve function by stimulating peripheral nervesto assess damage or function and or to map body receptive fields or theycan be used in conjunction with electrical and/or magnetic stimulationto overcome neural recruitment issues in clinical situations or forprosthetic devices. FIG. 20A shows a glove-like device although thiscould be a cell phone, pda, iPad, or video game controller. Peripheralnerve stimulation will modify brain activity in a way other than directapplication of ultrasound to the brain. FIG. 20B shows a picture ofhuman skin with anatomical illustration of hair and nerve endings fordetection of heat, cold, pain, proprioperception, etc.

In a like manner, methods of the present invention comprise stimulatingcranial nerves, which are nerves that are primarily outside the brainstructure itself, for example, but not as a limitation, the vestibularnerve, vestibulocochlear nerve, and the trigeminal nerve. The pulsed orcontinuous wave ultrasound can be delivered at acoustic frequenciesranging from 25 kHz to 50 MHz at intensities ranging from 30 mW/cm² to 1W/cm² from air- or water-matched transducers arranged as single elementsor phased arrays.

For example, a device for modulating peripheral or cranial nerveactivity of a human or animal user using ultrasound, may comprise anarticle configured to be placed on at least a portion of the body of theuser, and at least one ultrasonic transducer coupled to the article andconfigured to emit ultrasound, also referred to as acoustic energy,wherein the portion of the body of the user that is contacted by theultrasound is not the brain. The article may comprise a glove, a shoe, apiece of clothing, a scarf, a game controller, a cellular telephone, apersonal digital assistant, an iPad, a computer, a flexible material, ora non-flexible material. The article may be shaped to be adaptable tothe portion of the body to which the ultrasound is applied. There may beone or more ultrasound transducers coupled to the article, and at leastone ultrasound transducer is at least one of an ultrasonic emitter,piezoelectric transducer, piezocomposite transducer, piezopolymer, or acapacitive micromachined ultrasound transducer. The device may compriseat least one electromagnetic wave producing component. The device maycomprise a global positioning component. The device may comprise acontroller coupled to at least one ultrasonic transducer, wherein thecontroller controls waveform and power emitted by at least oneultrasonic transducer. The controller may be attached to the article.The controller may be located remote to the article. The device maycomprise a plurality of ultrasonic transducers positioned in an array oftransducers. An array may be in any configuration, for example an arrayof transducers may be a circular array of transducers. The device maycomprise components for focusing the acoustical energy to one or moresites in the brain of the user. Such focusing components are known, andinclude, but are not limited to, an acoustic hyperlens or acousticmetamaterial. The intensity of the acoustical energy is less than about500 mW/cm². The intensity of the acoustical energy is less than about100 W/cm². The frequency of the acoustical energy is between about 0.02MHz and 10.0 MHz. The frequency of the acoustical energy is betweenabout 25 kHz and 50 MHz.

The device may comprise at least one motion control component coupled tothe article, and/or may be coupled to at least one ultrasonictransducer, and a motion control component may be configured to changethe orientation of at least one transducer relative to its base. Thedevice may be configured for stimulation of peripheral nerves. Thedevice may be configured for stimulation of cranial nerves. For example,the device may stimulate cranial nerves which are distinct from brain,including, but not limited to, the vestibular nerve, thevestibulocochlear nerve or the trigeminal nerve. The device may providepulsed ultrasound waveforms, continuous ultrasound waveforms or both.

Example 7

Energy Production

A device of the present invention is powered when mechanical energygenerated by a physical activity such as walking, is converted toelectrical energy using piezopolymers or piezoelectric fiber compositeslocated in the shoes of the person wearing the ultrasound device. Theelectrical energy produced charges or re-charges the capacitive orbattery elements which are powering the ultrasound transducermicrocontrollers or other components of a device. The subject's shoecomprises PVDF piezopolymers and three microcontrollers for capturingthe energy that is generated during walking. The electrical energy thensupplies power to the device where it is stored in a capacitor orbattery. Two hours later, while undergoing training, the person uses thestored power to run the ultrasound phased array or single elementtransducers.

Example 8

Generation and Characterization of Pulsed US Waveforms

Immersion-type US transducers having a center frequency of 0.5 MHz(V301-SU, Olympus NDT, Waltham, Mass.) or 0.3 MHz (GS-300-D19, Ultran,State College, PA) were used to produce US waveforms. US pulses weregenerated by brief bursts of square waves (0.2 μs; 0.5 mV peak-to-peak)using an Agilent 33220A function generator (Agilent Technologies, Inc.,Santa Clara, Calif., USA). Square waves were further amplified (50 dBgain) using a 40 W ENI 240L RF amplifier. Square waves were deliveredbetween 0.25 and 0.50 MHz depending on the acoustic frequency desired.US pulses were repeated at a pulse repetition frequency by triggeringthe above-referenced function generator with square waves produced usinga second Agilent 33220A function generator.

The intensity characteristics of pulsed US stimulus waveforms werecharacterized by recording voltage traces produced by US pressure wavesusing a calibrated needle hydrophone (HNR 500, Onda Corporation,Sunnyvale, Calif., USA) and an Agilent DS06012A 100 MHz digitaloscilloscope connected to a PC. Intensity measurements were made fromtargeted points inside fresh ex vivo mouse heads corresponding to thebrain region targeted. The transcranial US waveforms were transmitted tointact brain circuits from US transducers using custom-designed acousticcollimators consisting of 3.0 or 4.7 mm (1 ml syringe) diameterpolyethylene tubing or 5.0 mm diameter tubing tapered to a 2.0 mmdiameter output aperture. Collimating guides were constructed sostimulated regions of the brain were in the far field of US transmissionpaths and filled with ultrasound coupling gel.

Using measurements recorded from calibrated hydrophones, severalacoustic intensity characteristics of pulsed US stimulus waveforms werecalculated based on published and industry accepted standards (NEMA,2004).

The pulse intensity integral (P//) was defined as

${P/}\;/={\int{\frac{p\; 2(t)}{z \circ}{dt}}}$

where p is the instantaneous peak pressure, Z₀ is the characteristicacoustic impedance in Pa s/m defined as ρc where ρ is the density of themedium, and c is the speed of sound in the medium. We estimated ρ to be1028 kg/m³ and c to be 1515 m/s for brain tissue based on previousreports (Ludwig, 1950). The spatial-peak, pulse-average intensity(/_(SPPA)) was defined as

$/_{SPPA}{= \frac{{P/}\;/}{PD}}$

where PD is the pulse duration defined as (t)(0.9P//−0.1 P//) 1.25 asoutlined by technical standards established by AIUM and NEMA (NEMA,2004).

The spatial-peak temporal-average intensity (/_(SPTA)) was definedas/_(SPTA)=P//(PRF), where PRF is equal to the pulse repetitionfrequency in hertz.

The mechanical index (MI) was defined as

${MI} = {\frac{P_{r}}{\sqrt{f}}.}$

In Vivo US Stimulation

Wild-type mice were used in accordance with animal-use protocolsapproved by the Institutional Animal Care and Use Committee at ArizonaState University. To conduct transcranial US stimulation of intact motorcortex, mice were anesthetized using a ketamine-xylazine cocktail (70mg/kg ketamine, 7 mg/kg xylazine) administered intraperitoneally. Thehair on the dorsal surface of the head over regions corresponding totargeted brain regions was trimmed. Mice were then placed in acustom-designed or Cunningham mouse stereo-tax. US transducers withaffixed collimators were lowered to points above the skin correspondingto brain regions using standard stereotactic coordinates. Collimators ortransducers were then placed on the surface of the skin above thetargeted brain region and coupled to the skin using ultrasound gel.Transcranial pulsed US stimulus waveforms were delivered to the targetedmotor cortex or hippocampus using standard TTL triggering protocols.Digital signal markers indicated the onset and length of US stimuluswaveforms. During some experiments, simultaneous electrophysiologicaldata were acquired (see below). Only in experiments where in vivoextracellular recordings of brain activity or brain temperature weremade was a craniotomy performed. Since cranial windows and electrodeinsertions were made at sites adjacent to angled US projection linestargeting specific brain regions, in these cases the US was stilltransmitted through skull bone, although not covered by overlying skin.All other experiments were conducted in wholly intact mice, except forsome mapping experiments that required retraction of the skin toidentify landmarks on the mouse skull. Following stimulation, animalswere either allowed to recover from anesthesia or processed as describedbelow.

Extracellular Recording

Extracellular activity was recorded using standard approaches withtungsten microelectrodes (500 kΩ to 1 MΩ, FHC, Inc., Bowdoin, Me., USA).Tungsten microelectrodes were driven to recording sites through cranialwindows (d=1 5 mm) based on stereotactic coordinates and confirmed byelectrophysiological signatures. Tungsten microelectrodes were connectedto a Medusa PreAmp (RA16PA; Tucker-Davis Technologies, Aluchua, Fla.,USA) and a multichannel neurophysiology workstation (Tucker-DavisTechnologies) or a 16 channel DataWave Experimenter and SciWorks(DataWave Technologies, Berthoud, Colo.) to acquire extracellularactivity. Raw extracellular activity in response to pulsed US wasacquired at a sampling frequency of 24.414 kHz in 10 s trial epochs. TheMUA signal was resampled at 1.017 kHz and bandpass filtered between 0.3to 6 kHz, the LFP signal was filtered between 1 and 120 Hz, widebandactivity was filtered between 0.001 and 10 kHz, gamma band activity wasfiltered between 40 and 100 Hz, and the SWP ripple band was filteredbetween 160 and 200 Hz. Data analyses were subsequently performedoffline.

EMG Recordings

Fine-wire EMG recordings were made using standard approaches and afour-channel differential AC amplifier (model 1700, A-M Systems, Inc.,Sequim, Wash., USA) with 10-1000 Hz band-pass filter and a 100× gainapplied. Electrical interference was rejected using a 60 Hz notchfilter. EMG signals were acquired at 2 kHz using a Digidata 1440A andpClamp or a 16 channel Data-Wave Experimenter and SciWorks. Briefly,small barbs were made in a 2 mm uncoated end of Teflon-coated steel wire(California Fine Wire, Co., Grover Beach, Calif., USA). Single recordingwires were then inserted into the appropriate muscles using a 30 gaugehypodermic syringe before being connected to the amplifier. Ground wireswere similarly constructed and subcutaneously inserted into the dorsalsurface of the neck.

Brain Temperature Recordings and Estimated Changes

Prior to US stimulation in some experiments, a small craniotomy (d≈2 mm)was performed on mouse temporal bone. Following removal of dura, a 0.87mm diameter thermocouple (TA-29, Warner Instruments, LLC, Hamden, Conn.,USA) was inserted into motor cortex through the cranial window. Thethermocouple was connected to a monitoring device (TC-324B, WarnerInstruments) and to a Digidata 1440A to record temperature (calibratedvoltage signal=100 mV/° C.) using pClamp.

The influence of US stimulus waveforms on brain temperature change wasestimated using a set of previously described equations valid for shortexposure times (O'Brien, 2007). Briefly, the maximum temperature change(ΔTmax) was estimated to be

$\Delta\; t_{\max}\frac{Q\;\Delta\; t}{C_{v}}$

where Δt is the pulse exposure time, where C_(v) is the specific heatcapacity for brain tissue ≈3.6 J/g/K (Cooper and Trezek, 1972), andwhere Q is the rate at which heat is produced defined by Nyborg (1981):

$\overset{\circ}{Q} = \frac{{ap}_{0}^{2}}{pc}$

where ρ is the density of the medium, c is the speed of sound in themedium as described above, where α is the absorption coefficient ofbrain (≈0.03 Np/cm for 0.5 MHz US; Goss et al., 1978), and p₀ is thepressure amplitude of US stimulus waveforms.

Data Analyses

All electrophysiological data (MUA, LFP, and EMG) were processed andanalyzed using custom-written routines in Matlab (The Mathworks, Natick,Mass., USA) or Clampfit (Molecular Devices). Single spikes were isolatedusing a standard thresholding window. Ultrasound waveformcharacteristics were analyzed using hydrophone voltage traces andcustom-written routines in Matlab and Origin (OriginLab Corp.,Northampton, Mass., USA). All histological confocal and transmittedlight images were processed and analyzed using ImageJ(http://rsb.info.nih.gov/ij/). Electron microscopy data were alsoquantified using ImageJ. All statistical analyses were performed usingSPSS (SPSS, Inc., Chicago, Ill., USA). Data shown are mean±SEM unlessindicated otherwise.

Example 9

Construction and Transmission of Pulsed Ultrasound Stimulus Waveformsinto Intact Brain Circuits

US stimulus waveforms were constructed and transmitted into the intactbrains of anesthetized mice (n=192; FIG. 11A). The optimal gains betweentranscranial transmission and brain absorption occurs for US at acousticfrequencies (f) <0.65 MHz (Hayner and Hynynen, 2001; White et al.,2006). Herein transcranial stimulus waveforms were constructed with UShaving f=0.25-0.50 MHz. Intensity characteristics of US stimuluswaveforms were calculated based on industry standards and publishedequations developed by the American Institute of Ultrasound Medicine,the National Electronics Manufacturers Association, and the UnitedStated Food and Drug Administration (NEMA, 2004; see above description).

Single US pulses contained between 80 and 225 acoustic cycles per pulse(c/p) for pulse durations (PD) lasting 0.16-0.57 ms. Single US Pulseswere repeated at pulse repetition frequencies (PRF) ranging from 1.2 to3.0 kHz to produce spatial-peak temporal-average intensities (/_(SPTA))of 21-163 mW/cm² for total stimulus duration ranging between 26 and 333ms. Pulsed US waveforms had peak rarefactional pressures (pr) of0.070-0.097 MPa, pulse intensity integrals (P//) of 0.017-0.095 mJ/cm²,and spatial-peak pulse-average intensities (/_(SPPA))of 0.075-0.229W/cm². FIGS. 11A and 11Billustrate the strategy developed forstimulating intact brain circuits with trans-cranial pulsed US. Theattenuation of US due to propagation through the hair, skin, skull, anddura of mice was <10% (FIG. 11C), and all intensity values reported werecalculated from US pressure measurements acquired using a calibratedhydrophone positioned with a micromanipulator inside fresh ex vivo mouseheads at locations corresponding to the brain circuit being targeted.

Example 10

Functional Stimulation of Intact Brain Circuits Using Pulsed Ultrasound

The influence of pulsed US on intact motor cortex was studied because itenables electrophysiological and behavioral measures of brainactivation. Local field potentials (LFP) and multiunit activity (MUA)were recorded in primary motor cortex (M1) while transmitting pulsed US(0.35 MHz, 80 c/p, 1.5 kHz PRF, 100 pulses) having an/_(SPTA)=36.20mW/cm² through acoustic collimators (d=4 7 mm) to the recordinglocations in anesthetized mice (n=8; FIGS. 12A and 12B). Pulsed UStriggered an LFP in M1 with a mean amplitude of −350.59±43.34 μV(FIG.2B, 25 trials each). The LFP was associated with an increase in thefrequency of cortical spikes (FIGS. 12C and 12D). This increase inspiking evoked by pulsed US was temporally precise and apparent within50 ms of stimulus onset (FIG. 12D). A broad range of pulsed US waveformswere found were equally capable of stimulating intact brain circuits asdiscussed below. Application of TTX (100 μM) to M1 (n=4 mice) attenuatedUS-evoked increases in cortical activity, indicating that transcranialUS stimulated neuronal activity mediated by action potentials (FIG.12B). These data provided evidence that pulsed US can be used todirectly stimulate neuronal activity and action potentials in intactbrain circuits.

Fine-wire electromyograms (EMG) and videos of muscle contractions inresponse to US stimulation of motor cortex in skin and skull-intact wereacquired in anesthetized mice. Using transcranial US to stimulate motorcortex, muscle contraction and movements were evoked in 92% of the micetested. The muscle activity triggered by US stimulation of motor cortexproduced EMG responses similar to those acquired during spontaneousmuscle twitches (FIG. 13A).

When using transducers directly coupled to the skin of mice, bilateralstimulation with transcranial US produced the near-simultaneousactivation of several muscle groups, indicated by tail, forepaw, andwhisker movements. By using acoustic collimators having an outputaperture of d=2.0, 3.0, or 4 7 mm and by making small (≈2 mm)adjustments to the positioning of transducers or collimators over motorcortex within a subject, the activity of isolated muscle groups wasdifferentially evoked. Despite these intriguing observations, it wasdifficult to reliably generate fine maps of mouse motor cortex using USfor brain stimulation. The likeliest explanation for this difficulty isthat the topographical/spatial segregation of different motor areasrepresented on the mouse cortex are below the resolution limits of US.

Example 11

The Influence of US Brain Stimulation Parameters on Motor CircuitResponse Properties

When bilaterally targeted to motor cortex, pulsed US (0.50 MHz, 100cycles per pulse, 1.5 kHz PRF, 80 pulses) having an/_(SPTA)=64.53 mW/cm²triggered tail twitches and EMG activity in the lumbosacrocaudalisdorsalis lateralis muscle with a mean response latency of 22.65±1.70 ms(n=26 mice). When unilaterally transmitted to targeted regions of motorcortex using a collimator (d=3 mm), pulsed US (0.35 MHz, 80 c/p, 2.5 kHzPRF, 150 pulses) having an/_(SPTA)=42.90 mW/cm² triggered an EMGresponse in the contralateral triceps brachii muscle with a meanresponse with latency of 20.88±1.46 ms (n=17 mice). With nearlyidentical response latencies (21.29±1.58 ms), activation of theipsilateral triceps brachii was also observed in ˜70% of theseunilateral stimulation cases. Although consistent from trial to trial(FIG. 13B), the EMG response latencies produced by US brain stimulationwere ≈10 ms slower those obtained using optogenetic methods andintracranial electrodes to stimulate motor cortex (Ayling et al., 2009).Several reports show that TMS also produces response latencies slowerthan those obtained with intracranial electrodes (Barker, 1999).Discrepancies among the response latencies observed between electricaland US methods of brain stimulation are possibly due to differences inthe time-varying energy profiles that these methods impact on braincircuits. The underlying core mechanisms of action responsible formediating each brain-stimulation method are additional factors likely toinfluence the different response times.

The baseline failure rate in obtaining US-evoked motor responses was <5%when multiple stimulus trials were repeated once every 4-10 s for timeperiods up to 50 min (FIG. 13B). As observed for response latencies inacute experiments, the peak amplitudes of EMG responses evoked bytranscranial pulsed US were stable across trial number (FIG. 13B). Inmore chronic situations, repeated US stimulation experiments wereperformed within individual subjects (n=5 mice) on days 0, 7, and 14using a trial repetition frequency of 0.1 Hz for 12-15 min each day. Inthese experiments, there were no differences in the peak amplitudes ofthe US-evoked EMG responses across days (day 0 mean peak EMGamplitude=40.26±0.99 μV, day 7=43.06±1.52 μV, day 14=42.50±1.42 μV;ANOVA F2 1303=1.47, p=0.23; FIG. 54A). These data demonstrate theability of transcranial US to successfully stimulate brain circuitactivity across multiple time periods spanning minutes (FIG. 13B) toweeks.

By examining EMG failure rates in eight mice, the success of achievingmotor activation was affected when stimulus trials were repeated in morerapid succession was studied. The mean EMG failure probabilitysignificantly increased (p<0.001) as the rate of US stimulus deliveryincreased from 0.25 to 5 Hz (FIG. 13C). These data suggest that brainstimulation with US may not be useful at stimulation frequencies above 5Hz.

Application of TTX to motor cortex blocked EMG activity, which indicatesthat pulsed US triggers cortical action potentials to drive peripheralmustcle contractions (n=4 mice; FIG. 13D). The intensities of US stimulistudied were <500 mW/cm², where mechanical bioeffects have been welldocumented in the absence of thermal effects (Dalecki, 2004; Dinno etal., 1989; O'Brien, 2007; ter Haar, 2007). To confirm these observationsin brain tissue, the temperature of motor cortex in response to USwaveforms having different pulse duration (PD) times were monitored.Equations for estimating thermal absorption of US in biological tissuesindicated that PD times are a critical factor for heat generation(O'Brien, 2007) and predict that 0.5 MHz US pulses exerting a p_(r) of0.097 MPa for a PD of 0.57 ms should produce a temperature increase of2.8×10-6° C. in brain. All US stimulus waveforms used in this study hadρ_(r) values <0.097 MPa and PD times <0.57 ms. None of the US waveformsused to stimulate cortex elicited a significant change in corticaltemperature within our 0.01° C. resolution limits (FIG. 13E). US pulseswith ρ_(r) values of 0.1 MPa and PD times >50 ms were required toproduce a nominal temperature change (ΔT) of 0.02° C. (FIG. 13E).

Acoustic frequencies and intensities across the ranges studiedinfluenced US-evoked EMG responses from the triceps brachii of mice(n=20). Motor cortex was stimulated using 20 distinct pulsed USwaveforms composed with different US frequencies (0.25, 0.35, 0.425, and0.5 MHz) and having varied intensities. The sequence of which differentwaveforms were used were randomized in individual stimulus trials toavoid order effects. Relative comparisons of EMG amplitudes acrossanimals can be influenced by many factors, including electrodeplacement, number of fibers recorded from, variation in noise levels,and differential fiber recruitment, which can be handled usingnormalization techniques to reduce intersubject variability. To examineUS-evoked EMG responses having the same dynamic range across animals,the peak amplitude of individual EMG responses was normalized to themaximum-peak amplitude EMG obtained for an animal and forced itsminimum-peak amplitude EMG response through zero. A two-way ANOVArevealed a significant main effect of US frequency on EMG amplitude,where lower frequencies produced more robust EMG responses (F31085=3.95, p<0.01; FIG. 14A). The two-way ANOVA also revealed asignificant main effect of intensity (/_(SPTA)) on EMG amplitudes (F19,1085=9.78, p<0.001; FIG. 4B), indicating that lower intensitiestriggered more robust EMG responses. The two-way ANOVA also revealed asignificant frequency x intensity interaction (F3, 1085=7.25, p<0.01;FIG. 4C), indicating differential effects of US waveforms on neuronalactivity as a function of frequency and intensity. The EMG responselatencies were not affected by either frequency or intensity (data notshown).

Example 12

Spatial Distribution of Brain Circuit Activation with TranscranialPulsed Ultrasound

To characterize the spatial distribution of US-evoked activity,functional activity maps were constructed using antibodies against c-fos(n=4 mice). To facilitate data interpretation, intact brain tissuehaving a relatively planar surface and prominent subcortical structureswas stimulated. The acoustic collimators (d=2 mm) were centered over theskull covering the right hemisphere from 1.2 mm to 3.2 mm of Bregma and0.5 mm to 2 5 mm lateral of the midline using stereo-tactic coordinates(FIG. 15A; Franklin and Paxinos, 2007). The smallest-diameter collimatorwas used to characterize the minimal resolution of the brain-stimulationmethod since it is expected that larger collimators will produce largerareas of brain activation. Pulsed US (0.35 MHz, 50 c/p, 1.5 kHz PRF, 500pulses) having an/_(SPTA)=36.20 mW/cm² was transmitted along a verticalaxis parallel to the sagittal plane through underlying brain regionsonce every 2 s for 30 min Following a 45 min recovery period, mice weresacrificed and their brains were harvested for histology.

Coronal sections from brain regions spanning +0.25 mm to 4.20 mm ofBregma were prepared (FIG. 15A). Individual sections spaced every 125 μmwere then immunolabeled using antibodies against c-fos and imaged usingtransmitted light microscopy. c-fos+ cell densities in 250×250 μmsquares were quantified for entire coronal sections, corrected fortissue shrinkage, and developed brain activity maps by plotting c-fos+cell densities in 250×250 μm pixels onto their corresponding anatomicallocations using mouse brain atlas plates (Franklin and Paxinos, 2007).Representative raw data and functional activity maps coding c-fos+ celldensity using a pseudocolor lookup table for visualization purposes areshown in FIGS. 15B-15D. The lateral resolution of pulsed US along therostral-caudal brain axis was estimated by analyzing regions of dorsalcortex (0.25-1.0 mm deep; 0.75-1.50 mm lateral of the midline) for eachcoronal section (FIGS. 15A-15D). An ANOVA comparing the mean c-fos+ celldensities for each 250×250 μm square region collapsed across animalsrevealed that pulsed US produced a significant increase in the densityof c-fos+ cells (ANOVA, F646=73.39, p<0.001; contralateral controlhemisphere mean c-fos+ cell density=16.29±0.20 cells/6.25×10-2 mm2compared to US stim=19.82±0.36 cells/6.25×10-2 mm2) Subsequent pairwisecomparisons of stimulated versus contralateral control cortex revealedthat US stimulation produced a significant increase in c-fos+ celldensities for a 1 5 mm region along the rostral-caudal axis (1.38 mm to−2.88 mm of Bregma) under the 2.0 mm diameter stimulation zone (FIG.15E). Similar analyses along the medial-lateral axis of dorsal cortexrevealed a significant increase (p<0.05) in c-fos+ cell densities for a2.0 mm wide region of brain tissue under the stimulation zone. Asmearing of elevated c-fos+ cell densities was observed lateral to thestimulation zone, which could be attributed to nonlinearities in theacoustic collimators the corticocortical lateral spread of activity,and/or slight lateral variations in the positioning of our collimators.

By examining the effects of pulsed US along the dorsal-ventral axiswithin the stimulation zone (0.5-2.5 mm medial to lateral; −1.2 to 3 2mm of Bregma), the density of c-fos+ cells was found to be significantlyhigher (p<0.05) compared to contralateral controls in the superficial1.0 mm of tissue. While there were trends of higher c-fos+ celldensities in some deeper nuclei of stimulated hemispheres, only onesignificant difference was observed in a deep-brain region.

The elevated c-fos here may have been produced by standing waves orreflections, since higher c-fos+ cell densities were generally observednear the skull base. It was expected to observe elevated c-fos+ levelsuniformly along the dorsal-ventral axis of stimulated regions due to thetransmission/absorption properties of US in brain tissue. For >1.5 mm ofthe 2.0 mm diameter cortical area targeted with US in these mappingstudies, regions deeper than 1 mm were ventral to dense white mattertracts (corpus callosum) in the brain. Interestingly, unmyelinatedC-fibers have been shown to be more sensitive to US than myelinated A∂fibers (Young and Henneman, 1961). Effectively blocking US-evokedactivity in subcortical regions, it was thought that low-intensity USfields may have been absorbed/scattered by dense white matter tracts inthese mapping studies as a function of the US transmission pathimplemented. It was possible to stimulate subcortical brain regions withtranscranial US by employing different targeting approaches.

Example 13

Remote Stimulation of the Intact Mouse Hippocampus Using TranscranialPulsed US

To address the issue of subcortical stimulation of deep brain circuits,the intact mouse hippocampus was used, since pulsed US waveforms havebeen shown to elicit action potentials and synaptic transmission inhippocampal slices (Tyler et al., 2008). Extracellular recordings ofUS-evoked activity in the CA1 stratum pyramidale (s.p.) cell body layerof dorsal hippocampus (n=7 mice) were performed. Prompted byobservations regarding the potential disruption of US fields by densewhite matter tracts, a targeting approach bypassing the dense whitematter of the corpus callosum was used when transmitting pulsed US tothe hippocampus.

An angled line of US transmission through the brain was used bypositioning acoustic collimators 50° from a vertical axis along thesagittal plane. The output aperture of collimators (d=2 mm) wereunilaterally centered over 4.5 mm of Bregma and 1.5 mm lateral of themidline (FIG. 16A). A 30° approach angle was used to drive tungstenmicroelectrodes to the CA1 s.p. region of hippocampus through cranialwindows (d=1.5 mm) centered approximately 1.0 mm of Bregma (FIG. 16A).Pulsed US (0.25 MHz, 40 cycles per pulse, 2.0 kHz PRF, 650 pulses)having an/_(SPTA)=84.32 mW/cm² reliably triggered an initial LFP with amean amplitude of 168.94±0.04 μV (50 trials each) and a mean responselatency of 123.24±4.44 ms following stimulus onset (FIG. 16B). Thisinitial LFP was followed by a period of after-discharge activity lasting<3 s (FIG. 16B). These short-lived after-discharges did not appear toreflect abnormal circuit activity as observed during epileptogenesis(Bragin et al., 1997; McNamara, 1994; Racine, 1972). In fact,hippocampal after-discharges lasting more than 10 s are indicative ofseizure activity (Racine, 1972).

Pulsed US produced a significant (p<0.01) increase in spike frequencylasting 1.73±0.12 s (FIG. 7B). Natural activity patterns in the CA1region of hippocampus exhibit gamma (40-100 Hz), sharp-wave (SPW)“ripple” (160-200 Hz), and other frequency-band oscillations reflectingspecific behavioral states of an animal (Bragin et al., 1995; Buzsaki,1989, 1996; Buzsaki et al., 1992). Sharp-wave ripples (≈20 msoscillations at ≈200 Hz) inCA1 result from the synchronized bursting ofsmall populations of CA1 pyramidal neurons (Buzsaki et al., 1992; Ylinenet al., 1995) and have recently been shown to underlie memory storage inbehaving rodents (Girardeau et al., 2009; Nakashiba et al., 2009). Onthe other hand, the consequences of gamma oscillations in the CA1 regionof the hippocampus are not as well understood but are believed to stemfrom the intrinsic oscillatory properties of inhibitory interneurons(Bragin et al., 1995; Buzsaki, 1996). By decomposing the frequencycomponents of wideband (1-10,000 Hz) activity patterns evoked by pulsedUS, it was found that all after-discharges contained both gammaoscillations and SWP ripple oscillations lasting <3 s (FIG. 16C). Thesedata demonstrated that pulsed US stimulated intact mouse hippocampuswhile evoking synchronous activity patterns and network oscillations;hallmark features of intrinsic hippocampal circuitry.

Brain-derived neurotrophic factor (BDNF) is one of the most potentneuromodulators of hippocampal plasticity, and its expression/secretionis known to be regulated by neuronal activity (Lessmann et al., 2003;Poo, 2001). BDNF protein expression levels in the hippocampus wereexamined following transcranial stimulation with pulsed US. Unilateralhippocampi of mice (n=7) were targeted and stimulated with pulsed US(0.35 MHz, 50 cycles per pulse, 1.5 kHz PRF, 500 pulses) havingan/_(SPTA)=36.20 mW/cm² every 2 s for 30 min. Following a 45 minrecovery period, mice were sacrificed and their brains removed,sectioned, and immunolabeled with antibodies against BDNF. Pulsed USinduced a significant increase in the density of BDNF+ puncta in CA1s.p. (contralateral control=149.64±11.49 BDNF+ puncta/7.5×10⁻² mm2 from0.61 mm2 CA1 region/mouse versus US stim=221.50±8.75 BDNF+puncta/7.5×10⁻² mm² from 0.61 mm2 CA1 region/mouse; t test, p<0.001;FIG. 16D). Similar significant increases were observed in the CA3 s.p.region (contralateral control =206.20±19.68 BDNF+ puncta/7.5×10⁻² mm2from 0.61 mm2 CA3 region/mouse versus US stim=324.82±27.94 BDNF+puncta/7.5×10⁻² mm² from 0.61 mm² CA3 region/mouse; t test, p<0.005;FIG. 16D). These data demonstrated that pulsed US can be used toremotely stimulate neuronal activity in the intact mouse hippocampus.The increased synchronous activity and elevated BDNF expression patternsproduced by pulsed US show that transcranial US can be used to promoteendogenous brain plasticity.

Example 14

Modifying Cognitive Performance

Referring to FIG. 17, a stimulus method for modifying cognitiveperformance was performed. Mice (n=4) were stimulated for five minuteswith transcranial ultrasound using the pulse parameters shown in FIG.17A, or sham treated the mice (n=3). Mice were allowed to rest for oneminute then they were placed in a Morris Water Maze (MWM) with a hiddenplatform and allowed to swim in the MWM until they a) found the escapeplatform or b) three minutes had elapsed at which point they were movedto the platform. The mice then rested 30 minutes before undergoing thestimulation or sham procedure again for a total of 4 trials per day forthree consecutive days. On day four, mice were not stimulated or shamtreated and were placed in the MWM where the platform had been removed.The time the mice spent swimming in the correct quadrant was recorded.Longer times in the correct quadrant indicated a better memory of wherethe escape platform had been located. As shown in the plot on the farright of FIG. 17B, stimulated mice spent less time in the correctquadrant indicating that had not learned or remembered where theplatform was as well as sham mice. The first two plots from left (17B)show stimulated mice take longer to find the escape platform across days(far left plot shows impaired learning). The slower task acquisitioncurve on the far left for stimulated animals shows it took the micelonger to learn the task compared to sham controls which had a fasteracquisition curve. Upon closer examination of trial to trial data withindays (middle plot), stimulated mice did not remember where the platformwas from trial to trial or from day to day as well as control mice. Thetwo figures at far left show stimulated mice took longer to locate theescape platform due to learning and memory impairments evoked by brainstimulation with ultrasound. More specifically, the data in FIG. 17Bshow that mice receiving hippocampal stimulation in the absence of taskcontext just prior to the context-dependent spatial learning task couldnot perform as well as sham controls. The data indicated that pulsedultrasonic stimulation of the hippocampus delivered close in time to atask requiring specific brain wave activity patterns to performoptimally was used to disrupt cognition by providing a masking patternof brain wave activity. Such a strategy can enable the use of pulsedultrasound to disrupt cognitive processes such as learning and memory.Brain regulation devices of various embodiments described herein can beused to deliver pulsed ultrasound to the intact hippocampus andassociated brain regions in order to modify cognitive processesincluding but not limited to disrupting normal cognition. These datashow that pulsed ultrasound can be delivered through brain regulationdevices disclosed herein to enhance cognitive processes or improvelearning and memory. An aspect of the invention comprises use of chronicrepeated ultrasound stimulation to increase the strength of synapsessuch that learning and memory is improved. Methods of the presentinvention comprise use of brain regulation devices to deliver ultrasoundtargeted to the hippocampus and modify cognitive performance byimpairing and or enhancing learning and memory, depending on the desiredneed to modify brain function and performance

Example 15

Use of Ultrasound for Enhancing Cognitive Processes

Referring to FIG. 18A-18B, methods disclosed herein were used forenhancing cognitive processes. Transcranial ultrasound was used tononinvasively enhance cognitive processes, such as learning and memory.Pulsed ultrasound can stimulate the intact hippocampus by drivingsynchronous oscillations in the gamma and sharp-wave ripple bands, whichare known to underlie hippocampal plasticity and learning and memory.

Transcranial ultrasound can upregulate BDNF signaling in thehippocampus. BDNF is one of the most potent modulators of brainplasticity. Very specific temporal patterns of brain activity arerequired to learn and remember. Disruption of such patterns with pulsedultrasound occurred when the brain was stimulated with a brainregulation device using ultrasound at times very close to the trainingtask. In order to enhance cognition, the intact hippocampus of mice(n=3) was stimulated with US for five minutes per day for 7 days priorto the mice undergoing training on the Morris Water Maze task. See FIG.18A for ultrasound parameters. The mice were not stimulated with USimmediately before training, instead mice were only stimulated on days1-7 prior to training. On day 8, mice were trained on the MWM task. Asshown in the left line plot of FIG. 18B, mice receiving stimulationlearned the MWM task faster than sham controls (n=3). Further,stimulated mice remembered where the platform was better than shamcontrols as indicated by the time spent in the correct quadrant when theescape platform was removed on day 4 (histogram right).

Example 16

Noninvasive Ultrasound Neuromodulation for Status Epilepticus (SE)

Status epilepticus (SE) refractory to conventional anti-epileptic drugstypically has a poor prognosis, but patients may recover well ifseizures can be stopped. Nearly 40% of patient with SE will berefractory to first line of therapy.

Recent pioneering studies illustrate the ability of pulsed ultrasound inremotely modulating intact brain circuit activity (Tufail et al., 2010),herein incorporated in its entirety. Transcranial pulsed ultrasound(TPU) can also synchronize intact hippocampal oscillations inhigh-frequency and gamma bands without producing damage or rise in braintemperature (Tufail et al., 2010). Though not wishing to be bound by anyparticular theory, it is thought that epileptic seizures are attributedto runaway excitation of certain brain circuitries and since electricaland magnetic brain stimulation have been shown capable of terminatingelectrographic seizure activity (Andrews, 2003; Hamani et al., 2009),pulsed or continuous wave US stimulation can be used interfere with orstop abnormal activity associated with SE.

FIG. 19 illustrates that transcranial pulsed ultrasound can be used tomodulate brain activity to study and or treat neurological diseases. (A)Shows EMG recordings in response to transcranial ultrasound stimulidelivered to the brain of normal mice in a continuous wave mode for 5seconds. The brain activity pattern stimulated by continuous wavetranscranial ultrasound is indicative of that observed during epilepticseizure activity. Such seizure activity patterns are known to occur forten seconds or longer following the onset of a brain stimulus as shownby the EMG traces in response to transcranial stimulation of braintissues with continuous wave ultrasound. Evoking such seizure activitypatterns can be helpful in studying epilepsy by mapping diseased orprone circuits, as well as by using ultrasound to modulate abnormalbrain activity patterns to screen for pharmacological compounds or genesuseful for treating such dysfunctional brain activity. The data in panel(A) triggered with continuous wave ultrasound showed that transcranialultrasound can influence brain activity depending on the ultrasoundstimulus waveform used and depending on the desired outcome. (B) A mouseis shown at left immediately after being injected with kainic acid toproduce a standard model of epilepsy. EMG activity before (top right)and after (bottom right) the onset of epileptic seizure activity isillustrated. The EMG traces on the bottom right show the presence ofseizure activity as indicated by the increased persistent EMG activitycompared to the pre-seizure trace on the top right. (C) EMG tracesshowing that brain stimulation achieved with transcranial ultrasound wasused to terminate seizure activity in a mouse model of epilepsy. Fourdifferent examples (FIG. 19 C) illustrate the delivery of transcranialultrasound was capable of quickly attenuating pronounced seizureactivity as indicated by the decreasing EMG amplitude soon after thedelivery of a transcranial ultrasound stimulus waveform. Such an effectof focused and or unfocused ultrasound on diseased brain activity can beadministered manually in response to seizures detected visually or byway of EEG or EMG activity.

In an embodiment of the present invention, methods and devices disclosedherein for the delivery of ultrasound to the brain can be controlledautomatically to provide US to the brain in response to seizure activitydetected by EEG, EMG, MEG, MRI, or other readout of brain activity. Anadvantage of using ultrasound to modulate abnormal brain activity suchas SE is that it is rapid and noninvasive. As taught here to treatepileptic seizure activity, the rapid response times and fast ability totreat diseased brain circuits with either focused or unfocusedultrasound provide a life saving treatment or may lead to improvedrecovery outcomes due to its rapid intervention to preventexcitotoxicity or other metabolic dysfunction arising from injuredbrain. When provided for the treatment of epilepsy or other diseased orinjury states such as those suffered by mild or severe traumatic braininjuries, ultrasound can provide a first line of treatment to dampenabnormal brain activity or to increase neuroprotective factor activity.Ultrasound for the treatment of diseased or injured brains can bedelivered by emergency response personnel or in neurocritical caresituations in the emergency room, operating room, a physician's office,a battlefield medical clinic, during transport to a medical facility, orat the scene of an accident. Here, the data on epilepsy are used as justone example of a disease where ultrasound can be rapidly applied to thehead for modulating brain activity in a rapid response manner to providebenefit.

1. (canceled)
 2. A device, the device comprising: a structure configuredto fit onto a subject's head; an array of either or both magnetictransducers or functional near-infrared spectroscopy (fNIRS) sensors; aplurality of phased array ultrasonic transducers coupled to thestructure and configured to emit ultrasound energy, wherein each phasedarray ultrasonic transducer comprises a plurality of concentricallyarranged piezoelectric active regions; and a controller configured tosense brain activity from the array of magnetic transducers orfunctional near-infrared spectroscopy (fNIRS) sensors and to coordinateapplication of ultrasound to one or more brain regions using theplurality of phased array ultrasonic transducers.
 3. The device of claim2, wherein the controller comprises a local microprocessor configured tomodulate one or more of an ultrasound waveform and a frequency,intensity or waveform characteristic to adjust the ultrasound beingdelivered based on sensed brain activity.
 4. The device of claim 2,further comprising a magnetoencephalography (MEG) or anelectroencephalography (EEG) sensor adapted to detect specificthalamocortical oscillations.
 5. The device of claim 2, furthercomprising controls configured to allow a user to control the device. 6.The device of claim 2, wherein the phased array ultrasonic transducersare configured to provide a predominantly non-thermal mechanism ofaction.
 7. The device of claim 2, wherein the phased array ultrasonictransducers are configured to deliver ultrasound energy at a frequencyin a range from 0.1 MHz to 1.5 MHz at a target tissue site.
 8. Thedevice of claim 2, wherein the phased array ultrasonic transducers areconfigured to deliver ultrasound energy with an intensity in a range ofabout 10 mW/cm² to about 500 mW/cm² at a target tissue site.
 9. Thedevice of claim 2, wherein the phased array ultrasonic transducers areconfigured to deliver ultrasound energy with a pulse duration in a rangefrom 100 to 10000 microseconds.
 10. The device of claim 2, wherein thestructure comprises a chassis for supporting the phased array ultrasonictransducers a desired position relative to the subject's head.
 11. Thedevice of claim 2, wherein the structure comprises a helmet.
 12. Thedevice of claim 2, wherein the structure further comprises a battery forpowering the plurality of phased array ultrasonic transducers.
 13. Thedevice of claim 2, wherein the structure further comprises one or morecooling units.
 14. The device of claim 13, wherein the cooling unitcomprises a cooling unit which functions as an ultrasound coupling padto aid in transmission of ultrasound waves.
 15. The device of claim 2,further comprising one or more power sources, components fortransmitting or receiving data, and components for remote activation ofthe plurality of phased array ultrasonic transducers.
 16. The device ofclaim 2, wherein the plurality of concentrically arranged piezoelectricactive regions comprises a circular array configured to focus anacoustic beam.
 17. The device of claim 2, wherein the plurality ofconcentrically arranged piezoelectric active regions comprises aplurality of concentric rings that are each divided into quadrants. 18.The device of claim 2, further comprising an acoustic hyperlens or anacoustic metamaterial for focusing an acoustic beam.
 19. A device, thedevice comprising: a structure configured to fit onto a subject's head;an array of functional near-infrared spectroscopy (fNIRS) sensorscoupled to the structure; a plurality of phased array ultrasonictransducers coupled to the structure and configured to emit ultrasoundenergy, wherein each phased array ultrasonic transducer comprises aplurality of concentrically arranged piezoelectric active regions; and acontroller configured to sense brain activity from the array offunctional near-infrared spectroscopy (fNIRS) sensors and to coordinateapplication of ultrasound to one or more brain regions using theplurality of phased array ultrasonic transducers.
 20. A device, thedevice comprising: a structure configured to fit onto a subject's head;an array of magnetic transducers coupled to the structure; a pluralityof phased array ultrasonic transducers coupled to the structure andconfigured to emit ultrasound energy, wherein each phased arrayultrasonic transducer comprises a plurality of concentrically arrangedpiezoelectric active regions; and a controller configured to sense brainactivity from the array of magnetic transducers and to coordinateapplication of ultrasound to one or more brain regions using theplurality of phased array ultrasonic transducers.